Arch Gynecol Obstet DOI 10.1007/s00404-014-3602-0
GENERAL GYNECOLOGY
Ultrasonography-guided multidrug stratification interventional therapy for cesarean scar pregnancy Dejiao Kong • Xiaoqiu Dong • Yunfeng Qi
Received: 8 June 2014 / Accepted: 3 December 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose To explore the clinical value of ultrasonography-guided multidrug stratification interventional therapy for cesarean scar pregnancy (CSP). Methods Aspiration of gestational sac fluid, injection of methotrexate in the sac, injection of homeostatic agent and pituitrin in the uterine muscle layer, and injection of triple anti-inflammatory drugs around the uterus in 12 patients with CSP. The lesion volume, serum b-hCG level, and blood flow were observed. Results The mean b-hCG level continued to decrease posttreatment, and the greatest reduction occurred in week 1. The mean number of days needed for serum b-hCG values to decrease to normal level was 39.1 ± 10.1 days. Mass volumes reduced and the mean number of days for the masses to disappear was 24.6 ± 14.1 days. The blood flow around the lesions continued to decrease. Conclusions Ultrasonography-guided multidrug interventional therapy for CSP is a new, safe, effective, minimally invasive method. Keywords Cesarean scar pregnancy Ultrasonographyguided Interventional therapy Multidrug Stratification
deliveries in China in recent years, as well as the wide application of vaginal ultrasonography, the incidence of CSP and the number of diagnosed cases have been gradually increasing [2–4]. Delayed and inappropriate treatment for CSP could lead to serious hemorrhage, uterine rupture, hysterectomy, and even life-threatening events [5– 8]. Currently, traditional conservative treatment methods for CSP include medication, dilation and curettage, and uterine artery embolization [9]. However, systemic medication requires long hospitalization and has serious side and toxic effects. Direct dilation and curettage could cause hemorrhage. Uterine artery embolization is costly and leaves large wounds [10–17]. Generally, traditional treatment for this condition is associated with problems such as overtreatment for a minor condition or unsatisfactory outcome. Therefore, proper and simple treatment methods are needed. In this study, we summarized and analyzed the interventional therapies used in 12 CSP patients who were hospitalized in the Fourth Hospital of Harbin Medical University, China, between 2010 and 2014. We also explored the clinical value of ultrasonography-guided local interventional therapy for CSP.
Materials and methods Introduction Cesarean scar pregnancy (CSP) is a rare type of ectopic pregnancy [1]. Yet with the increasing number of cesarean
D. Kong X. Dong (&) Y. Qi Department of Ultrasonography, The Fourth Hospital of Harbin Medical University, Yiyuan Str 37, Harbin 150001, Heilongjiang, People’s Republic of China e-mail: [email protected]
Between March 2010 and July 2014, 12 patients were admitted to the Obstetrics and Gynecology Department of our hospital. They were diagnosed with CSP by vaginal ultrasonography and voluntarily chose Ultrasonographyguided interventional therapy. Patients aged 28–38 years, including ten with a history of one cesarean section and two with a history of repeated cesarean sections, were included. The time between this gestation and the last cesarean section was 17–127 months. The patients’
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gestational age was 40–77 days. Vaginal bleeding occurred in four patients. The pretreatment serum b-hCG level was 4,545–103,720 mIU/mL. Gestational sacs were observed at the cesarean section incision scars in all patients using vaginal ultrasonography. The diameters were 1.6–6.4 cm. Yolk sacs were also seen in all the patients. Primitive ventricle or embryonic heart pulsations were observed in eight cases (Fig. 1a, b). Peripheral blood flow was grade 2 in four cases and grade 3 in eight cases (Table 1). None of the patients had hepatic or renal diseases or a methotrexate allergy history. Within 3 days after the operation, five patients underwent dilation and curettage, including one who underwent ultrasonography-guided interventional therapy after failed uterine artery embolization. We used the MyLab 90 color Doppler sonography unit (Esaote SpA, Genoa, Italy) attached with a 3.0–9.0-MHz transvaginal probe (EC123), as well as a puncture needle holder and 20-cm long 18-gauge disposable percutaneous puncture needles (Hakko, Nagano, Japan). The embryocidal drug used, methotrexate, was obtained from Hengrui Medicine Co. (Jiangsu, Lianyungang, China). The
homeostatic agent used was hemocoagulase from Ahno Pharmaceutical Co. (Liaoning, Jinzhou, China). The drug used to promote uterus contraction was vasopressin from Harvest Pharmaceutical Co., Ltd (Shanghai, China). Gentamicin sulfate and dexamethasone sodium phosphate (Tianjin Pharmaceutical Group, Tianjin, China), and chymotrypsin (Hainan Jinrui Pharmaceutical Co., Haikou, Hainan, China) were used as antibiotics and anti-inflammatory drugs, respectively. Laboratory tests including electrocardiographic activity, clotting time, serum b-hCG level, and liver and kidney functions were performed on all patients 1 day before the operation. Regular vaginal ultrasonographic examinations were performed, recording the sizes, locations, structures, and peripheral blood flow of the gestational sacs, as well as the uterine muscle thickness between the gestational sac and bladder. The patients and their families were verbally informed of the treatment process, as well as the existing risks and key technologies, and provided informed consent. All the patients underwent vaginal ultrasonography-guided treatment. The puncture needle was inserted in the
Fig. 1 Vaginal ultrasonographic images before and after interventional therapy. a Gestational and yolk sacs were seen at the uterine scar. b Representative image of the gestational sac indicated a live embryo with regular cardiac activity. c Ultrasonography-guided
puncture needle entered the gestational sac. d The mass disappeared 4 weeks after treatment. UT indicates uterus, GS indicates gestational sac, YS indicates yolk sac, bpm indicates beats per minute, HR indicates heart rate, N indicates needle point
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Arch Gynecol Obstet Table 1 Patients’ clinical data, ultrasound features, and outcome indices (n = 12) Before treatment Basic clinical data
After treatment –
Age, years
32.8 ± 4.0
–
History of cesarean section, no. of times Gestation period, days
1.3 ± 0.6
–
Time since last cesarean section, months
69.8 ± 34.6
Number of pregnancies
3.0 ± 1.0
–
Time of vaginal bleeding, days
6.1 ± 2.3
–
55.1 ± 11.7
Gestational sac/mass on ultrasonography Maximum diameter of gestational sac, cm
3.3 ± 1.4
–
Yolk sac apparent, n
12
–
Fetal heart apparent, n
8
–
Time to disappearance of mass, days
–
24.6 ± 14.1
spotty or thin rodlike blood vessels in the lesion); 2, medium blood flow (3 or 4 spotty blood vessels or 1 major blood vessel with a length approximating or exceeding the radius of the lesion); and 3, rich blood flow (C5 spotty blood vessels or 2 long blood vessels). Calculation standard for mass volume: Volume (cm3) = (minimum diameter)2 (cm2) 9 maximum diameter (cm)/2. For posttreatment masses with clear boundaries, regions with uneven echoes on two-dimensional ultrasonography were used. For those with unclear boundaries, colored blood flow images were used to select areas with abnormal blood flow for measurement. The mean of the three measurements was used. SPSS 13.0 statistical package (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. Measurement data were presented as X ± SD. The analysis of variance and t test was used to analyze differences between means. P \ 0.01 indicates statistically significant difference.
Results
Serum b-hCG level, mIU/mL Initial level before treatment
43,407 ± 31,221
–
Transient increase 3 days after treatment
–
5/ 10,090 ± 15,178
Time to serum b-hCG normalization, days
–
39.1 ± 10.1
Referred for surgery, n
–
0
Pelvic bleeding after treatment, n
–
0
Data are presented as number and X ± SD (standard deviation) b-hCG indicates b-human chorionic gonadotropin
gestational sac in the uterine isthmus muscle layer through the vaginal fornix (Fig. 1c). The gestational sac fluid was aspirated before 40–60 mg of methotrexate was injected into the gestational sac. An area surrounding the gestational sac with abundant blood supply was injected with the 2 KU of hemocoagulase and 5–10 mg of vasopressin. Two groups of triple anti-inflammatory drugs (320 mg of gentamicin sulfate, 10 mg of dexamethasone sodium phosphate, and 8,000 U of chymotrypsin) were injected around the gestational sac and in the pelvic cavity before withdrawing the needle. Compression hemostasis was applied. Serum b-hCG levels were measured, and ultrasonography was performed at 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, and 5 weeks after treatment, respectively. This technique was approved by the ethics committee of the hospital. Blood flow to the gestational sac or mass was graded according to the semiquantitative method of Adler [18]: 0, no blood flow in the lesion; 1, small blood flow (1 or 2
The mean age of the patients was 32.8 ± 4.0 years. Most of them had one previous cesarean section. The mean time since the last cesarean section was 69.8 ± 34.6 months. The mean maximum diameter of the gestational sac was 3.3 ± 1.4 cm. The mean number of days for serum b-hCG levels to drop to normal level was 39.1 ± 10.1 days. The mean number of days for masses to disappear was 24.6 ± 14.1 days. No pelvic hemorrhage or failed conservative treatment occurred (Table 1). The mean serum b-hCG level showed a decreasing trend posttreatment. The reduction was greatest in week 1, with a slope of -2.1 (Fig. 2a). The difference between the levels in week 5 after treatment and those before treatment was statistically significant (P \ 0.01). The serum b-hCG level in seven cases showed a continuous decreasing trend on day 3 after treatment; Whereas transient increases were noted in Cases 1, 2, 8, 10 and 12 and the mean increase was 10,090 ± 15,178 mIU/mL, then the levels kept decreasing from week 1 to 5, with the maximum reduction as high as 40,387 mIU/mL. Three days after treatment, the masses with clear boundaries were found in eight cases, and those with unclear boundaries were found in four cases. The original gestational sac cavities in ten cases disappeared and those in two cases had clearly shrunken and changed shape. The mean posttreatment mass volume showed a decreasing trend, with the highest decrease in week 1, which had a slope of -0.9 (Fig. 2b). In week 3, the masses in Cases 1, 8, and 11 disappeared partly or completely. In week 4, the mass in Cases 2–6, 9 and 12 disappeared or almost disappeared (Fig. 1d). The difference between the mass
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Fig. 2 Changes in clinically relevant parameters before and after interventional treatment. a Changes in mean serum b-hCG level (mIU/mL). b Changes in mean mass volume (cm3). c Changes in mass blood flow
volumes in week 5 and day 3 after treatment was statistically significant (P \ 0.01). The blood flow around the masses continued to decrease after treatment(Fig. 2c). In week 5, four cases had grade 0, seven had grade 1, and one had grade 2 blood flow. Most of the cases had grade 0 or 1 blood flow, which was a significantly lower grade than that before treatment.
Discussion CSP is the implantation of the gestational sac at the uterine incision scar after cesarean section, surrounded by uterine muscle layers and fibrous scar tissues. It is a rare type of ectopic pregnancy [2]. CSP may occur 0.5–12 years after cesarean section and is a long-term complication of cesarean section [5]. The reported CSP incidence is one per 1,800–2,216 of all pregnancies and 6.1 % of all ectopic pregnancies [7]. If diagnosis is delayed or not made, or if treatment is not appropriate, CSP could lead to serious complications such as hemorrhage, uterine rupture, and other life-threatening events. Currently, clinical treatment methods frequently used for CSP include medication,
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dilation and curettage, uterine artery embolization, and surgery [9, 19–23]. The first local drug treatment for CSP, which was introduced by Godin [24], opened up a new route for interventional therapies in treating CSP. Local administration of methotrexate can increase the drug concentration in the gestational sac, improve efficacy, and reduce systemic adverse effects. In particular, its effectiveness in treating ectopic pregnancies with embryonic heart pulsation has been widely accepted [6, 7, 25]. In this study, we selected 12 patients with CSP and applied local multidrug stratification interventional therapy. The mean pretreatment serum b-hCG level was 43,407 ± 31,221 mIU/mL. The mean number of days for the posttreatment serum b-hCG levels to drop to normal level was 39.1 ± 10.1 days, whereas the reported time after treatment with methotrexate alone was 65 ± 44.4 days [1]. In comparison, the number of days for the serum b-hCG levels to drop to the normal level was clearly lower using this method than single-drug treatment. The reduction in serum b-hCG levels was the largest in week 1, with a slope of -2.1. However, on day 3, the reduction rate of the serum b-hCG level was small, with a mean value of 41,596 ± 25,818 mIU/mL. Transient increases were noted in Cases 1, 2, 8, 10 and 12. Compared with the pretreatment levels, the posttreatment levels showed a mean increase of 10,090 ± 15,178 mIU/mL on day 3. Within 5 weeks after treatment, the mean serum bhCG level showed a continuously decreasing trend (Fig. 2a), and showed a statistically significant difference compared with the pretreatment value (P \ 0.01). Serum b-hCG level is considered an important parameter of trophoblastic biological activity and reflects the degree of trophoblastic cell viability, growth rate, and infiltration depth [26]. A high serum b-hCG level also indicates an increased risk of pelvic hemorrhage. In week 1, the reduction in the serum b-hCG levels was the greatest, indicating a significant decline in trophoblastic cell viability and the highest apoptosis rate. The serum b-hCG level in some cases transiently increased on day 3. On one hand, this could be due to the patients’ sensitivity toward methotrexate. When the drug acted fast, local administration led to fast embryo termination, trophoblastic cells died in a short period, and large amounts of serum b-hCG entered the blood stream and resulted in a transient increase [27]. On the other hand, measurement of the serum b-hCG level pretreatment and treatment was separated by a period during which serum b-hCG level could keep on increasing. To prevent large amounts of serum b-hCG transiently entering into the blood from trophoblastic cell death, we injected a hemocoagulase and pituitrin in the areas of the uterine muscle layer with abundant blood supply. This restricted the transient increase in serum b-hCG level.
Arch Gynecol Obstet
Pretreatment gestational sac maximum diameters were 1.6–6.4 cm, equivalent to 5–10 weeks of pregnancy. After treatment, the original gestational sac cavities disappeared in 10 cases and showed a significant reduction in size and deformation in two cases. The local echoes of the masses increased and were uneven. The area of muscle tissues receiving relatively normal blood supply increased in the early stages of the treatment. Posttreatment mass volumes gradually decreased. The mean mass volume was 10.0 ± 6.9 cm3 on day 3 and 7.2 ± 6.9 cm3 in week 1. The mass volume showed the highest reduction rate in week 1, with a slope of -0.9 (Fig. 2b). The difference between the mass volumes in week 5 and day 3 after treatment was statistically significant (P \ 0.01). Methotrexate could lead to extensive and fast villi necrosis. Local mass edema resulted in relatively large mass volumes on day 3 after treatment. In this treatment, we administered triple anti-inflammatory drugs through diffusion injection around the gestational sac and in the pelvic cavity. This effectively reduced the production of proinflammatory substances, local exudation, and surrounding tissue adhesion. It also increased metabolism and clearance of blood clots and necrotic tissues. The efficacy of the drugs improved during the course of treatment. The rate of reduction in mass volumes increased. The mean number of days for masses to disappear was 24.6 ± 14.1 days after treatment. There has been no report in the literature on this subject, to our knowledge. In this study, the pretreatment blood flow around the gestational sacs was grade 2 in four cases and grade 3 in eight cases. The blood flow around the masses continued to decrease from day 3 to week 5 after treatment. In week 5, four cases had grade 0, seven had grade 1, and one had grade 2 blood flow. Most of the patients had grade 0 or 1 blood flow, which was significantly lower than that before treatment (Fig. 2c). The hemocoagulase and pituitrin induced contraction and occlusion of the nourishing vascular network, which is abundant around the mass. Uterine muscle fiber tissue contraction also enhanced vasoconstriction function, potentially reducing the risk of vascular rupture and hemorrhage around the mass. Pituitrin can also cause uterine muscle fiber tissues contraction, pressing the remaining gestational tissues to the relatively weak side of the uterine cavity, thus allowing dilation and curettage to be performed easily by the obstetrician and gynecologist. In this study, dilation and curettage was performed on the masses after interventional therapy in five cases. In conclusion, Ultrasonography-guided multidrug stratification interventional therapy for CSP is a new, safe, effective, minimally invasive method. This method can effectively kill the embryo, accelerate the speed of serum b-hCG level reduction, and promote the fast absorption of the mass. The most significant clinical value is in
preventing uterine hemorrhage to improve the success rate of conservative treatments for CSP, thus serving as a convenient and appropriate new method. Conflict of interest All authors have read and approved the content, and agree to submit for consideration for publication in the journal. We state our study does not have a financial relationship with the organization that sponsored the research .We have had full control of all primary data and agree to allow your Journal to review our data if requested.
References 1. Seow KM, Wang PH, Huang LW, Hwang JL (2013) Transvaginal sono-guided aspiration of gestational sac concurrent with a local methotrexate injection for the treatment of unruptured cesarean scar pregnancy. Arch Gynecol Obstet 288:361–366 2. Rotas MA, Haberman S, Levgur M (2006) Cesarean scar ectopic pregnancies: etiology, diagnosis, and management. Obstet Gynecol 107:1373–1381 3. Jin H, Zhou J, Yu Y, Dong M (2004) Intramural pregnancy: a report of 2 cases. J Reprod Med 49:569–572 4. Maymon R, Halperin R, Mendlovic S, Schneider D, Vaknin Z, Herman A, Pansky M (2004) Ectopic pregnancies in caesarean section scars: the 8 year experience of the one medical centre. Hum Reprod 19:278–284 5. Nonaka M, Toyoki H, Imai A (2006) Cesarean section scar pregnancy may be the cause of serious hemorrhage after firsttrimester abortion by dilatation and curettage. Int J Gynaecol Obstet 95:50–51 6. Jurkovic D, Hillaby K, Woelfer B, Lawrence A, Salim R, Elson CJ (2003) First-trimester diagnosis and management of pregnancies implanted into the lower uterine segment cesarean section scar. Ultrasound Obstet Gynecol 21:220–227 7. Seow KM, Huang LW, Lin YH, Lin MY, Tsai YL, Hwang JL (2004) Cesarean scar pregnancy: issues in management. Ultrasound Obstet Gynecol 23:247–253 8. Fylstra DL (2002) Ectopic pregnancy within a cesarean scar: a review. Obstet Gynecol Surv 57:537–543 9. Bignardi T, Condous G (2010) Transrectal ultrasound-guided surgical evacuation of cesarean scar ectopic pregnancy. Ultrasound Obstet Gynecol 35:481–485 10. Wang JH, Xu KH, Lin J, Jian YX, Rui LW (2009) Methotrexate therapy for cesarean section scar pregnancy with and without suction curettage. Fertil Steril 92:1208–1213 11. Wang CN, Chen CK, Wang HS, Chiueh HY, Soong YK (2007) Successful management of heterotopic cesarean scar pregnancy combined with intrauterine pregnancy after in vitro fertilizationembryo transfer. Fertil Steril 88(3):706.e13–706.e16 12. Chiang AJ, La V, Chou CP, Wang PH, Yu KJ (2011) Ectopic pregnancy in a cesarean section scar. Fertil Steril 95:2388–2389 13. Monteagudo A, Minior VK, Stephenson C, Monda S, TimorTritsch IE (2005) Non-surgical management of live ectopic pregnancy with ultrasound-guided local injection: a case series. Ultrasound Obstet Gynecol 25:282–288 14. Barnhart K, Hummel AC, Sammel MD, Menon S, Jain J, Chakhtoura N (2007) Use of a ‘‘2-dose’’ regimen of methotrexate to treat ectopic pregnancy. Fertil Steril 87(2):250–256 15. Wang CB, Tseng CJ (2006) Primary evacuation therapy for cesarean scar pregnancy: three new cases and review. Ultrasound Obstet Gynecol 27:222–226 16. Arslan M, Pata O, Dilek TU, Aktas A, Aban M, Dilek S (2005) Treatment of viable cesarean scar ectopic pregnancy with suction curettage. Int J Gynaecol Obstet 89:163–166
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Arch Gynecol Obstet 17. Li C, Li C, Feng D, Jia C, Liu B, Zhan X (2011) Transcatheter arterial chemoembolization versus systemic methotrexate for the management of cesarean scar pregnancy. Int J Gynaecol Obstet 113(3):178–182 18. Adler DD, Carson PL, Rubin JM, Quinn-Reid D (1990) Doppler ultrasound color flow imaging in the study of breast cancer: preliminary findings. Ultrasound Med Biol 16:553–559 19. Li H, Guo HY, Han JS, Wang JL, Xiong GW, Shen J, Zhang JJ (2011) Endoscopic treatment of ectopic pregnancy in a cesarean scar. J Minim Invasive Gynecol 18:31–35 20. Yin X, Su S, Dong B, Ban Y, Li C, Sun B (2012) Angiographic uterine artery chemoembolization followed by vacuum aspiration: an efficient and safe treatment for managing complicated cesarean scar pregnancy. Arch Gynecol Obstet 285:1313–1318 21. He M, Chen MH, Xie HZ, Yao SZ, Zhu B, Feng LP, Wu YP (2011) Transvaginal removal of ectopic pregnancy tissue and repair of uterine defect for caesarean scar pregnancy. BJOG 118:1136–1139 22. Einenkel J, Stumpp P, Kosling S, Horn LC, Michael H (2005) A misdiagnosed case of caesarean scar pregnancy. Arch Gynecol Obstet 271:178–181
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23. Hwu YM, Hsu CY, Yang HY (2005) Conservative treatment of caesarean scar pregnancy with transvaginal needle aspiration of the embryo. BJOG 112(6):841–842 24. Godin PA, Bassil S, Donnez J (1997) An ectopic pregnancy developing in a previous cesarian section scar. Fertil Steril 67:398–400 25. Halperin R, Vaknin Z, Schneider D, Yaron M, Herman A (2003) Conservative management of ectopic pregnancy with fetal cardiac activity by combined local (sonographically guided) and systemic injection of methotrexate. Gynecol Obstet Invest 56:148–151 26. Natale A, Candiani M, Merlo D, Lzzo S, Gruft L, Busacca M (2003) Human chorionic gonadotropin level as a predictor of trophoblast infiltration into the tubal wall in ectopic pregnancy: a blinded study. Fertil Steril 79(4):981–986 27. Dai Q, Wang LL, Shao XH, Wang SM, Dong XQ (2012) Clinical effectiveness of multiple-drug injection treatment in unruptured ectopic pregnancies. J Ultrasound Med 31:1627–1634
GENERAL GYNECOLOGY
Ultrasonography-guided multidrug stratification interventional therapy for cesarean scar pregnancy Dejiao Kong • Xiaoqiu Dong • Yunfeng Qi
Received: 8 June 2014 / Accepted: 3 December 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose To explore the clinical value of ultrasonography-guided multidrug stratification interventional therapy for cesarean scar pregnancy (CSP). Methods Aspiration of gestational sac fluid, injection of methotrexate in the sac, injection of homeostatic agent and pituitrin in the uterine muscle layer, and injection of triple anti-inflammatory drugs around the uterus in 12 patients with CSP. The lesion volume, serum b-hCG level, and blood flow were observed. Results The mean b-hCG level continued to decrease posttreatment, and the greatest reduction occurred in week 1. The mean number of days needed for serum b-hCG values to decrease to normal level was 39.1 ± 10.1 days. Mass volumes reduced and the mean number of days for the masses to disappear was 24.6 ± 14.1 days. The blood flow around the lesions continued to decrease. Conclusions Ultrasonography-guided multidrug interventional therapy for CSP is a new, safe, effective, minimally invasive method. Keywords Cesarean scar pregnancy Ultrasonographyguided Interventional therapy Multidrug Stratification
deliveries in China in recent years, as well as the wide application of vaginal ultrasonography, the incidence of CSP and the number of diagnosed cases have been gradually increasing [2–4]. Delayed and inappropriate treatment for CSP could lead to serious hemorrhage, uterine rupture, hysterectomy, and even life-threatening events [5– 8]. Currently, traditional conservative treatment methods for CSP include medication, dilation and curettage, and uterine artery embolization [9]. However, systemic medication requires long hospitalization and has serious side and toxic effects. Direct dilation and curettage could cause hemorrhage. Uterine artery embolization is costly and leaves large wounds [10–17]. Generally, traditional treatment for this condition is associated with problems such as overtreatment for a minor condition or unsatisfactory outcome. Therefore, proper and simple treatment methods are needed. In this study, we summarized and analyzed the interventional therapies used in 12 CSP patients who were hospitalized in the Fourth Hospital of Harbin Medical University, China, between 2010 and 2014. We also explored the clinical value of ultrasonography-guided local interventional therapy for CSP.
Materials and methods Introduction Cesarean scar pregnancy (CSP) is a rare type of ectopic pregnancy [1]. Yet with the increasing number of cesarean
D. Kong X. Dong (&) Y. Qi Department of Ultrasonography, The Fourth Hospital of Harbin Medical University, Yiyuan Str 37, Harbin 150001, Heilongjiang, People’s Republic of China e-mail: [email protected]
Between March 2010 and July 2014, 12 patients were admitted to the Obstetrics and Gynecology Department of our hospital. They were diagnosed with CSP by vaginal ultrasonography and voluntarily chose Ultrasonographyguided interventional therapy. Patients aged 28–38 years, including ten with a history of one cesarean section and two with a history of repeated cesarean sections, were included. The time between this gestation and the last cesarean section was 17–127 months. The patients’
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gestational age was 40–77 days. Vaginal bleeding occurred in four patients. The pretreatment serum b-hCG level was 4,545–103,720 mIU/mL. Gestational sacs were observed at the cesarean section incision scars in all patients using vaginal ultrasonography. The diameters were 1.6–6.4 cm. Yolk sacs were also seen in all the patients. Primitive ventricle or embryonic heart pulsations were observed in eight cases (Fig. 1a, b). Peripheral blood flow was grade 2 in four cases and grade 3 in eight cases (Table 1). None of the patients had hepatic or renal diseases or a methotrexate allergy history. Within 3 days after the operation, five patients underwent dilation and curettage, including one who underwent ultrasonography-guided interventional therapy after failed uterine artery embolization. We used the MyLab 90 color Doppler sonography unit (Esaote SpA, Genoa, Italy) attached with a 3.0–9.0-MHz transvaginal probe (EC123), as well as a puncture needle holder and 20-cm long 18-gauge disposable percutaneous puncture needles (Hakko, Nagano, Japan). The embryocidal drug used, methotrexate, was obtained from Hengrui Medicine Co. (Jiangsu, Lianyungang, China). The
homeostatic agent used was hemocoagulase from Ahno Pharmaceutical Co. (Liaoning, Jinzhou, China). The drug used to promote uterus contraction was vasopressin from Harvest Pharmaceutical Co., Ltd (Shanghai, China). Gentamicin sulfate and dexamethasone sodium phosphate (Tianjin Pharmaceutical Group, Tianjin, China), and chymotrypsin (Hainan Jinrui Pharmaceutical Co., Haikou, Hainan, China) were used as antibiotics and anti-inflammatory drugs, respectively. Laboratory tests including electrocardiographic activity, clotting time, serum b-hCG level, and liver and kidney functions were performed on all patients 1 day before the operation. Regular vaginal ultrasonographic examinations were performed, recording the sizes, locations, structures, and peripheral blood flow of the gestational sacs, as well as the uterine muscle thickness between the gestational sac and bladder. The patients and their families were verbally informed of the treatment process, as well as the existing risks and key technologies, and provided informed consent. All the patients underwent vaginal ultrasonography-guided treatment. The puncture needle was inserted in the
Fig. 1 Vaginal ultrasonographic images before and after interventional therapy. a Gestational and yolk sacs were seen at the uterine scar. b Representative image of the gestational sac indicated a live embryo with regular cardiac activity. c Ultrasonography-guided
puncture needle entered the gestational sac. d The mass disappeared 4 weeks after treatment. UT indicates uterus, GS indicates gestational sac, YS indicates yolk sac, bpm indicates beats per minute, HR indicates heart rate, N indicates needle point
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Arch Gynecol Obstet Table 1 Patients’ clinical data, ultrasound features, and outcome indices (n = 12) Before treatment Basic clinical data
After treatment –
Age, years
32.8 ± 4.0
–
History of cesarean section, no. of times Gestation period, days
1.3 ± 0.6
–
Time since last cesarean section, months
69.8 ± 34.6
Number of pregnancies
3.0 ± 1.0
–
Time of vaginal bleeding, days
6.1 ± 2.3
–
55.1 ± 11.7
Gestational sac/mass on ultrasonography Maximum diameter of gestational sac, cm
3.3 ± 1.4
–
Yolk sac apparent, n
12
–
Fetal heart apparent, n
8
–
Time to disappearance of mass, days
–
24.6 ± 14.1
spotty or thin rodlike blood vessels in the lesion); 2, medium blood flow (3 or 4 spotty blood vessels or 1 major blood vessel with a length approximating or exceeding the radius of the lesion); and 3, rich blood flow (C5 spotty blood vessels or 2 long blood vessels). Calculation standard for mass volume: Volume (cm3) = (minimum diameter)2 (cm2) 9 maximum diameter (cm)/2. For posttreatment masses with clear boundaries, regions with uneven echoes on two-dimensional ultrasonography were used. For those with unclear boundaries, colored blood flow images were used to select areas with abnormal blood flow for measurement. The mean of the three measurements was used. SPSS 13.0 statistical package (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. Measurement data were presented as X ± SD. The analysis of variance and t test was used to analyze differences between means. P \ 0.01 indicates statistically significant difference.
Results
Serum b-hCG level, mIU/mL Initial level before treatment
43,407 ± 31,221
–
Transient increase 3 days after treatment
–
5/ 10,090 ± 15,178
Time to serum b-hCG normalization, days
–
39.1 ± 10.1
Referred for surgery, n
–
0
Pelvic bleeding after treatment, n
–
0
Data are presented as number and X ± SD (standard deviation) b-hCG indicates b-human chorionic gonadotropin
gestational sac in the uterine isthmus muscle layer through the vaginal fornix (Fig. 1c). The gestational sac fluid was aspirated before 40–60 mg of methotrexate was injected into the gestational sac. An area surrounding the gestational sac with abundant blood supply was injected with the 2 KU of hemocoagulase and 5–10 mg of vasopressin. Two groups of triple anti-inflammatory drugs (320 mg of gentamicin sulfate, 10 mg of dexamethasone sodium phosphate, and 8,000 U of chymotrypsin) were injected around the gestational sac and in the pelvic cavity before withdrawing the needle. Compression hemostasis was applied. Serum b-hCG levels were measured, and ultrasonography was performed at 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, and 5 weeks after treatment, respectively. This technique was approved by the ethics committee of the hospital. Blood flow to the gestational sac or mass was graded according to the semiquantitative method of Adler [18]: 0, no blood flow in the lesion; 1, small blood flow (1 or 2
The mean age of the patients was 32.8 ± 4.0 years. Most of them had one previous cesarean section. The mean time since the last cesarean section was 69.8 ± 34.6 months. The mean maximum diameter of the gestational sac was 3.3 ± 1.4 cm. The mean number of days for serum b-hCG levels to drop to normal level was 39.1 ± 10.1 days. The mean number of days for masses to disappear was 24.6 ± 14.1 days. No pelvic hemorrhage or failed conservative treatment occurred (Table 1). The mean serum b-hCG level showed a decreasing trend posttreatment. The reduction was greatest in week 1, with a slope of -2.1 (Fig. 2a). The difference between the levels in week 5 after treatment and those before treatment was statistically significant (P \ 0.01). The serum b-hCG level in seven cases showed a continuous decreasing trend on day 3 after treatment; Whereas transient increases were noted in Cases 1, 2, 8, 10 and 12 and the mean increase was 10,090 ± 15,178 mIU/mL, then the levels kept decreasing from week 1 to 5, with the maximum reduction as high as 40,387 mIU/mL. Three days after treatment, the masses with clear boundaries were found in eight cases, and those with unclear boundaries were found in four cases. The original gestational sac cavities in ten cases disappeared and those in two cases had clearly shrunken and changed shape. The mean posttreatment mass volume showed a decreasing trend, with the highest decrease in week 1, which had a slope of -0.9 (Fig. 2b). In week 3, the masses in Cases 1, 8, and 11 disappeared partly or completely. In week 4, the mass in Cases 2–6, 9 and 12 disappeared or almost disappeared (Fig. 1d). The difference between the mass
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Fig. 2 Changes in clinically relevant parameters before and after interventional treatment. a Changes in mean serum b-hCG level (mIU/mL). b Changes in mean mass volume (cm3). c Changes in mass blood flow
volumes in week 5 and day 3 after treatment was statistically significant (P \ 0.01). The blood flow around the masses continued to decrease after treatment(Fig. 2c). In week 5, four cases had grade 0, seven had grade 1, and one had grade 2 blood flow. Most of the cases had grade 0 or 1 blood flow, which was a significantly lower grade than that before treatment.
Discussion CSP is the implantation of the gestational sac at the uterine incision scar after cesarean section, surrounded by uterine muscle layers and fibrous scar tissues. It is a rare type of ectopic pregnancy [2]. CSP may occur 0.5–12 years after cesarean section and is a long-term complication of cesarean section [5]. The reported CSP incidence is one per 1,800–2,216 of all pregnancies and 6.1 % of all ectopic pregnancies [7]. If diagnosis is delayed or not made, or if treatment is not appropriate, CSP could lead to serious complications such as hemorrhage, uterine rupture, and other life-threatening events. Currently, clinical treatment methods frequently used for CSP include medication,
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dilation and curettage, uterine artery embolization, and surgery [9, 19–23]. The first local drug treatment for CSP, which was introduced by Godin [24], opened up a new route for interventional therapies in treating CSP. Local administration of methotrexate can increase the drug concentration in the gestational sac, improve efficacy, and reduce systemic adverse effects. In particular, its effectiveness in treating ectopic pregnancies with embryonic heart pulsation has been widely accepted [6, 7, 25]. In this study, we selected 12 patients with CSP and applied local multidrug stratification interventional therapy. The mean pretreatment serum b-hCG level was 43,407 ± 31,221 mIU/mL. The mean number of days for the posttreatment serum b-hCG levels to drop to normal level was 39.1 ± 10.1 days, whereas the reported time after treatment with methotrexate alone was 65 ± 44.4 days [1]. In comparison, the number of days for the serum b-hCG levels to drop to the normal level was clearly lower using this method than single-drug treatment. The reduction in serum b-hCG levels was the largest in week 1, with a slope of -2.1. However, on day 3, the reduction rate of the serum b-hCG level was small, with a mean value of 41,596 ± 25,818 mIU/mL. Transient increases were noted in Cases 1, 2, 8, 10 and 12. Compared with the pretreatment levels, the posttreatment levels showed a mean increase of 10,090 ± 15,178 mIU/mL on day 3. Within 5 weeks after treatment, the mean serum bhCG level showed a continuously decreasing trend (Fig. 2a), and showed a statistically significant difference compared with the pretreatment value (P \ 0.01). Serum b-hCG level is considered an important parameter of trophoblastic biological activity and reflects the degree of trophoblastic cell viability, growth rate, and infiltration depth [26]. A high serum b-hCG level also indicates an increased risk of pelvic hemorrhage. In week 1, the reduction in the serum b-hCG levels was the greatest, indicating a significant decline in trophoblastic cell viability and the highest apoptosis rate. The serum b-hCG level in some cases transiently increased on day 3. On one hand, this could be due to the patients’ sensitivity toward methotrexate. When the drug acted fast, local administration led to fast embryo termination, trophoblastic cells died in a short period, and large amounts of serum b-hCG entered the blood stream and resulted in a transient increase [27]. On the other hand, measurement of the serum b-hCG level pretreatment and treatment was separated by a period during which serum b-hCG level could keep on increasing. To prevent large amounts of serum b-hCG transiently entering into the blood from trophoblastic cell death, we injected a hemocoagulase and pituitrin in the areas of the uterine muscle layer with abundant blood supply. This restricted the transient increase in serum b-hCG level.
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Pretreatment gestational sac maximum diameters were 1.6–6.4 cm, equivalent to 5–10 weeks of pregnancy. After treatment, the original gestational sac cavities disappeared in 10 cases and showed a significant reduction in size and deformation in two cases. The local echoes of the masses increased and were uneven. The area of muscle tissues receiving relatively normal blood supply increased in the early stages of the treatment. Posttreatment mass volumes gradually decreased. The mean mass volume was 10.0 ± 6.9 cm3 on day 3 and 7.2 ± 6.9 cm3 in week 1. The mass volume showed the highest reduction rate in week 1, with a slope of -0.9 (Fig. 2b). The difference between the mass volumes in week 5 and day 3 after treatment was statistically significant (P \ 0.01). Methotrexate could lead to extensive and fast villi necrosis. Local mass edema resulted in relatively large mass volumes on day 3 after treatment. In this treatment, we administered triple anti-inflammatory drugs through diffusion injection around the gestational sac and in the pelvic cavity. This effectively reduced the production of proinflammatory substances, local exudation, and surrounding tissue adhesion. It also increased metabolism and clearance of blood clots and necrotic tissues. The efficacy of the drugs improved during the course of treatment. The rate of reduction in mass volumes increased. The mean number of days for masses to disappear was 24.6 ± 14.1 days after treatment. There has been no report in the literature on this subject, to our knowledge. In this study, the pretreatment blood flow around the gestational sacs was grade 2 in four cases and grade 3 in eight cases. The blood flow around the masses continued to decrease from day 3 to week 5 after treatment. In week 5, four cases had grade 0, seven had grade 1, and one had grade 2 blood flow. Most of the patients had grade 0 or 1 blood flow, which was significantly lower than that before treatment (Fig. 2c). The hemocoagulase and pituitrin induced contraction and occlusion of the nourishing vascular network, which is abundant around the mass. Uterine muscle fiber tissue contraction also enhanced vasoconstriction function, potentially reducing the risk of vascular rupture and hemorrhage around the mass. Pituitrin can also cause uterine muscle fiber tissues contraction, pressing the remaining gestational tissues to the relatively weak side of the uterine cavity, thus allowing dilation and curettage to be performed easily by the obstetrician and gynecologist. In this study, dilation and curettage was performed on the masses after interventional therapy in five cases. In conclusion, Ultrasonography-guided multidrug stratification interventional therapy for CSP is a new, safe, effective, minimally invasive method. This method can effectively kill the embryo, accelerate the speed of serum b-hCG level reduction, and promote the fast absorption of the mass. The most significant clinical value is in
preventing uterine hemorrhage to improve the success rate of conservative treatments for CSP, thus serving as a convenient and appropriate new method. Conflict of interest All authors have read and approved the content, and agree to submit for consideration for publication in the journal. We state our study does not have a financial relationship with the organization that sponsored the research .We have had full control of all primary data and agree to allow your Journal to review our data if requested.
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