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Serum hCG decline following salpingotomy or salpingectomy for extrauterine pregnancy
European Journal of Obstetrics & Gynecology and Reproductive Biology 53 (1994) 59-64
Serum hCG decline following salpingotomy or salpingectomy for extrauterine pregnancy P. Hellemans, J. Gerris*, M. Joostens, S. van der Meer, P. Verdonk, M. Francx Department
of Obstetrics. Gynecology and Fertility,
Middelheim
Hospital.
Lindendreef
I, B-2020 Antwerp, Belgium
(Accepted 30 September 1993)
Abstract Twenty-five women with ectopic pregnancy were surgically treated, fifteen by conservative salpingotomy and ten by radical salpingectomy. All patients showed a clinically normal postoperative course. Serum human chorionic gonadotropin (hCG) levels were determined serially before and after the surgical procedure until non-pregnant values (< 5 mI.U./ml) were reached. Serum hCG decline was compared between patients treated by salpingotomy versus salpingectomy, using calculated hCG half-life times. We observed a significantly slower decline of serum hCG levels during the early phase of hCG disappearance in patients treated by salpingotomy versus patients treated by salpingectomy. Key
words:
Ectopic
pregnancy;
Salpingectomy;
Salpingotomy;
1. Introduction During the last two decades, the management of ectopic pregnancy has undergone major developments. Because of the availability of improved diagnostic techniques, the typical clinical situation of severe hemorrhagic shock due to hemoperitoneum entailing immediate laparotomy has been gradually replaced by well-planned, often laparoscopic, surgery allowing conservative management of the tubes and ovaries [l-4]. However, the use of these conservative techniques has given rise to the risk of the so-called persistent ectopic pregnancy. Persistent ectopic pregnancy can be defined as a pathological entity, caused by the continual growth of trophoblastic tissue, requiring additional treatment after initial conservative management [5-71. In order to diagnose this pathological condition postoperatively, monitoring of serum human chorionic gonadotropin (hCG) has become an integral part of the follow-up treatment of women who suffer an ectopic pregnancy and are treated either surgically or medically [2,3,6,8]. The disappearance curves and times of hCG from the
* Corresponding 0028-2243/94/$07.00 SSDI
author.
0
0028-2243(93)01709-3
1994
Elsevier
Science Ireland
Serum hCG half-life time
plasma have been studied after delivery [9], after intravenous administration [lo], after spontaneous and induced abortion [ 1l- 131, after removal of ectopic pregnancy [6,13- 191 and after second-trimester hysterectomy [12]. These studies have shown a positive correlation between initial preoperative serum hCGlevels and the disappearance time [9,12,13,15,18,19]. However, these studies did not agree with respect to the length of the hCG half-life times and the possible correlation between the initial serum hCG value and the hCG half-life [9,14,17,18]. All authors who studied the metabolism of hCG in man agree on the biphasic pattern of its regression curve, consisting of a fast initial component in the first 24-48 h, followed by a slow component [9,10,14,15,17]. Several authors described hCG disappearance from plasma following systemic or local methotrexate treatment [20-281, following local prostaglandin treatment [29-321 and during expectant management [33-351 as non-surgical treatment modalities for ectopic pregnancy. Globally, much slower hCG disappearances are being observed following nonsurgical approach compared with surgical management. Histopathologic observations of developing tubal ectopic pregnancies have shown that the trophoblastic tissue rapidly invades the lamina propria and the
Ltd. All rights reserved.
P. Hellemans et al. /Eur. J. Obstet. Gynecol. Reprod. Biol. 53 (1994) 59-64
60
muscularis of the tube and begins to grow at an extratubal but still retroperitoneal site [36]. In another study invasiveness of the trophoblast appeared to be limited to the lamina propria and tubal rupture was proposed to be secondary to localized distension and vascular compromise with hemorrhagic necrosis [37]. The invading character of the developing trophoblast and its aggressiveness towards the muscularis of the tube appears to be related to the location of the ectopic gestation, i.e. ampullary or isthmic [38,39]. Taking into account the above mentioned histopathologic considerations, one could easily imagine small amounts of viable trophoblastic tissue staying behind in the wall of the fallopian tube after successful surgical approach. These small amounts of residual active trophoblast could theoretically continue to produce hCG before finally degenerating. This could cause a delay in hCG clearance, resulting in higher hCG half-life times when compared with situations where a more radical surgery is performed and all trophoblastic tissue completely removed. The aim of our study is to compare serum hCG clearance in women undergoing radical salpingectomy versus technically complete salpingotomy for extrauterine pregnancy, taking into account the different components of the hCG disappearance curve in man. 2. Materials and methods Twenty-five patients with a preoperative diagnosis of ectopic pregnancy underwent surgical treatment: ten were treated by salpingectomy, three laparoscopically and seven through laparotomy, and fifteen were treated by salpingotomy, nine laparoscopically and six through laparotomy. Salpingotomy was performed using CO? laser equipment (Oplimas, Carl Zeiss, Germany), followed by trophoblast extraction, extensive washing of the tubal cavity and aspiration of the extracted trophoblastic tissue. The decision whether conservative or radical surgery was carried out was based on the presence and severity of hemoperitoneum, the physician’s experience with operative videolaparoscopy and microsurgical procedures, the tuboperitoneal status and, finally, previous history of ectopic gestation in the affected fallopian tube. In all patients uterine curettage was performed at the same time. In all patients serial quantitative serum hCG determinations were carried out immediately preoperatively, 24 h postoperatively, 48 h postoperatively and from then on every 4 days until serum hCG levels reached nonpregnant values (< 5 mI.U./ml). In all patients half-life times for serum hCG were calculated by the expression [9]: 0.693
TN = ~
r
where r=
log cont. at time a - log cont. at time b 0.434 x time interval
In each patient, the half-life time for serum hCG was calculated for the complete postoperative follow-up period until serum hCG reached non-pregnant values, and separately for the first 48 h postoperatively (initial phase - fast component) and for the time interval between 48 h postoperatively and the moment serum hCG level reached non-pregnant values (~5 mI.U./ml) (late phase - slow component). We compared the calculated half-life times for the above defined time intervals between the women treated by salpingectomy versus those treated by salpingotomy. To evaluate the effect of the height of the initial serum hCG level on hCG half-life time we compared in both the salpingectomy group and in the salpingotomy group, the calculated half-life time in women with an initial serum hCG level >2000 mI.U./ml with the calculated half-life time in women with an initial hCG level <2000 mI.U./ml for all three previously defined time intervals of the follow-up period. Serum hCG determinations were carried out on sera freshly separated from peripheral blood. We used a commercial kit for the radioimmunological determination of @-hCG subunit (RIA-gnost hCG, Behringwerke AG, Marburg, Germany) based on the principle of a sandwich assay using monoclonal mouse anti-&hCG ( ‘251-labelled) antibody and solid phase monoclonal mouse anti-&hCG antibody. RIA-gnost hCG has been standardized against the first IRP WHO (75/537) in mI.U./ml. Statistical analysis was carried out using Wilcoxon signed ranks test for non-parametric values. 3. Results All patients showed normal postoperative courses and no case of persistent ectopic pregnancy was observed in the conservatively treated group. No chorionic villi were observed in any of the endometrial contents presented for pathological examination. In all patients the diagnosis of ectopic pregnancy was confirmed by pathologic examination of the removed fallopian tube following salpingectomy or removed tubal contents following salpingotomy. Initial hCG level (mean f S.E.M.) in the salpingotomy group and in the salpingectomy group were 2281 f 442 mI.U./ml (n = 15) and 4498 f 1803 mI.U./ml (RIO), respectively, which are statistically comparable values (P > 0.10). Initial hCG levels from both groups are shown in Table 1. In both treatment groups, hCG half-life times during
61
P. Hellemans et al. /Eur. J. Obsret. Gynecol. Reprod. Biol. 53 (1994) 59-64 Table 1 Initial hCG levels (mI.U./ml) from the salpingotomy and from the salpingectomy group (n = IO) Salpingotomy
Salpingectomy
2500 4230 2150 6980 2560 2140 2960 3170 1470 35 1920 1400 I800 784
2270 3370 I7 600 10700 7010 2620 1850 868 232 813
group
(n = 15)
II0
the early phase of hCG disappearance were significantly shorter than during the late phase: 26.9 + 6.1 h vs. 62.1 f 12.1 h in the salpingotomy group (P = 0.0019) and 15 f 1.7 h vs. 52.8 f 5.3 h in the salpingectomy group (P = 0.012). We did not find a statistically significant difference in serum hCG half-life times between patients treated by
salpingectomy versus patients treated by salpingotomy for the total follow-up period (early and late phase taken together) (P = 0.51) and for the late phase (P = 0.57). However, for the early phase, hCG half-life time was significantly longer in the salpingotomy group than in the salpingectomy group: 26.9 f 6.1 h vs. 15 f 1.7 h (P = 0.04), respectively (Fig. 1). The level of the initial serum hCG value (>2000 mI.U./ml as compared with ~2000 mI.U./ml) did not appear to influence the course of hCG disappearance in either treatment group (salpingotomy or salpingectomy) in either of the previously defined time intervals (Fig. 1). Disappearance curves for serum hCG in both treatment groups are depicted in Fig. 2. One patient treated by laparoscopic lasersalpingotomy for a left-sided preampullary ectopic gestation and having an initial hCG level of 2500 mI.U./ml showed a very slow hCG decline during the late phase of hCG regression with a half-life time of 212 h. Another patient treated by laparoscopic lasersalpingotomy with an initial hCG level of 2150 mI.U./ml showed a very slow decline over the early phase of hCG regression with a half-life time of 102 h. Both patients showed normal postoperative courses. The data on these two patients were also included in the statistical comparisons.
% of titer
t1
2 80
bun)
6.
@
;i
tl 2
Ihours) @
81 60
4.
0
I
I
I
40
72
96
I
120
I
144
168
192
216
hours postoperative
20 0
t1 2
I
24
% of titer
*O 60
‘4
(hours)4. 0
20 0
a ~~0.05
q EarlyPhase qLatePhase
Fig. I. Histogrammatic representation of hCG half-life times (mean f S.E.M.): A Salpingotomy (left) versus salpingectomy (right), for the early phase (P = 0.04), the late phase (P = 0.57) and the total phase (P = 0.51). B Salpingotomy group: initial hCG >2000 mI.U./ml (left) versus <2000 mI.U./ml (right) for early phase (P = 0.35), late phase (P = 0.50) and total phase (P = 0.22). C Salpingectomy group: initial hCG >2000 mI.U./ml (left) versus < 2000 mI.U./ml (right) for early phase (P = 0.71). late phase (P = I) and total phase (P = 0.29).
24
48
72
96
120
144
168
192
216
hours postoperative
Fig. 2. Percentage of preoperative hCG concentration remaining atter surgical procedure in the salpingotomy group (n = 15) (upper pannel) and in the salpingectomy group (n = IO) (lower pannel).
62
P. Hellemans et al. /Eur. J. Ohsret. Gynecol. Reprod. Biol. 53 (19941 59-64
4. Discussion
The disappearance of hCG from the bloodstream after termination of pregnancy, whether intrauterine or extrauterine, is initially a rapid exponential decline with a half-life of hCG between 5 and 13 h, followed by a slower continually decreasing rate of between 22 and 52 h [9,10,14,15,17]. Holtz [14] described P-hCG clearance following salpingotomy for ectopic gestation in three patients by plotting to a percentage of the initial titer converted, postoperative &hCG values versus time from operation. Half-life values for sequential 24-h intervals after operation were 12.9, 19.4 and 51.7 h, respectively. La Sala et al. [ 171investigated hCG decline in 41 women undergoing salpingectomy for ectopic gestation. They described hCG clearance by a biexponential model and concluded their observations to be similar to the observations by Pouly et al. [ 181following laparoscopic conservative surgical management. Pouly et al. [18] studied the drop in hCG levels in 76 patients following laparoscopic conservative surgical management for ectopic gestation and presented a nomogram for the postoperative follow-up after laparoscopic treatment for ectopic pregnancy relying on the hCG clearance rate. They observed a hCG half-life time of 19.4 h in the first 48 postoperative hours and a half-life time of 63.9 h in the subsequent days. They stated the observed drop in hCG after conservative treatment using laparoscopy is similar to the one known to occur after conservative treatment using laparotomy. Steier et al. [13] studied 35 cases of ectopic pregnancy treated by laparotomy. They also observed a biphasic hCG regression pattern, but did not specify whether salpingotomy or salpingectomy was performed. Kamrava et al. [ 151 studied the length of time serum hCG remains detectable following removal of ectopic pregnancy in a group of seven women who underwent salpingectomy or partial resection of the involved fallopian tube and in a group of nine women who underwent salpingotomy or Iimbrial expression. They concluded the initial titer of hCG to be a significant factor in determining the length of time it remains postoperatively detectable in the serum. They also observed a biphasic regression pattern in both study groups with an initial fast component followed by a slow component. Despite the fact that hCG regression curves in both groups seem very comparable, no comparison on a statistical basis was carried out in this study [15]. Kontoravdis et al. [16] studied the regression of hCG levels in nine patients undergoing salpingectomy for active tubal pregnancy and six patients undergoing salpingotomy for regressed tubal pregnancies. Mean hCG values in both groups showed the same exponential regression pattern but mean values of the hormone in both groups showed significant differences during the whole observed time interval. Letterie
and Ramirez [19] studied the clearance time for serum hCG in ectopic pregnancy by monitoring the interval between surgical intervention and complete disappearance of hCG in 15 patients with ruptured tubal ectopic pregnancy managed by salpingectomy and in 10 patients with unruptured, ectopic pregnancy managed by salpingotomy. Mean initial serum hCG levels differed significantly between both groups. Higher initial serum hCG levels were observed in the salpingectomy group. They concluded duration of clearance to be correlated primarily to the initial hCG concentration. This explains the slower hCG clearance observed in the salpingectomy group. They also presented a nomogram for postoperative hCG surveillance following salpingotomy. In a prospective randomized clinical trial comparing management of unruptured ectopic gestation by linear salpingotomy following laparotomy versus laparoscopy, a similar &hCG regression pattern in both study groups was observed [40]. In our study we compared 15 patients successfully treated by salpingotomy for ectopic gestation with 10 patients treated by salpingectomy. All patients showed normal postoperative courses and no case of persistent ectopic pregnancy was observed in the conservatively treated group. We calculated half-life times for different time intervals, i.e. early phase, late phase and total follow-up period. In both study groups we observed hCG clearance consists of more than one component, i.e. a fast component followed by a slow component, as previously shown by different authors [9,10,14,15,17,18]. Initial serum hCG levels did not appear to be a determining factor for hCG half-life time. We did not find a significant difference in P-hCG half-life times between women in the salpingectomy group and women in the salpingotomy group during the late phase and the total follow-up period. However, a significant difference was found in the early phase, where a slower hCG regression pattern was observed in the salpingotomy group. Several authors have declared postoperative hCG regression patterns to be similar in women undergoing tube-conserving surgery (salpingotomy, fimbrial expression), compared with women undergoing radical surgery (salpingectomy, segmental resection) for ectopic pregnancy [15-171. However, by taking into account the biphasic pattern of the hCG regression curve in man in our statistical comparisons, we demonstrated a significantly slower hCG decline following salpingotomy versus salpingectomy for ectopic gestation in the first 48 postoperative hours. This could be explained by the postoperative persistence of small amounts of residual viable trophoblastic tissue in the tubal wall following conservative surgery. This residual trophoblastic tissue could be held responsible for ongoing hCG production before secondarily degenerating, resulting in a higher hCG half-life time in the early postoperative period.
P. ffeffemans
et al. /Eur.
63
J. Obsfet. Gynecol. Reprod. Biol. 53 (1994) 59-64
When considering our observations, this purely theoretical reasoning seems applicable only to the early phase of hCG disappearance but not to the total follow-up period and to the late phase of hCG disappearance. Two patients treated by salpingotomy showed much longer hCG half-life times compared with the other patients. This also could be due to incomplete removal of
12
trophoblastic tissue at surgical intervention, responsible for ongoing hCG production and higher half-life times before finally degenerating. The observed phenomenon should be discriminated from the so-called persistent ectopic pregnancy, a pathological entity caused by the continual growth of trophoblastic tissue, requiring additional treatment after initial conservative management. No case of persistent ectopic pregnancy was observed in our study group. A study by Vermesh et al. [6] showed that early detection of persistent ectopic pregnancy following conservative surgical management, relying on postoperative progesterone and beta-hCG surveillance, is only possible from the sixth postoperative day onwards. From our observations we conclude hCG clearance to be significantly slower in the first 48 postoperative hours following successful salpingotomy, compared with salpingectomy for ectopic gestation. This observation could be explained by the postoperative persistence of secondarily degenerating, viable trophoblastic tissue in the wall of the fallopian tube in the early postoperative period following conservative surgical management.
14
13
15
16
17
18
19
20
21
22
5. References 23 1 2 3 4 5
6
DeCherney AH, Romero R, Naftolin F. Surgical management of unruptured ectopic pregnancy. Fertil Steril 1981; 35: 21-24. Leach RE, Ory SJ. Modern management of ectopic pregnancy. J Reprod Med 1989; 34: 324-338. Vermesh M. Conservative management of ectopic gestation. Fertil Steril 1989; 51: 559-567. Zorn JR, Risque2 F, Cedard L. Ectopic pregnancy. Curr Opinion Obstet Gynecol 1992; 4: 238-245. Bell OR, Awadalla SG, Mattox JH. Persistent ectopic syndrome: a case report and literature review. Obstet Gynecol 1987; 69: 521-523. Vennesh M, Silva PD, Sauer MV, Vargyas JM, Lobo RA. Persistent tubal ectopic gestation patterns of circulating beta-human chorionic gonadotropin and progesterone, and management options. Fertil Steril 1988; 50: 584-588. Stock R. Persistent tubal pregnancy. Obstet Gynecol 1991; 77: 267-270. Johnson TRB, Sanborn JR, Wagner KS, Compton AA. Gonadotropin surveillance following conservative surgery for ectopic pregnancy. Fertil Steril 1980; 33: 207-208. Midgley AR, Jr., Jaffe RB. Regulation of human gonadotropins II. Disappearance of human chorionic gonadotropin following delivery. J Clin Endocrinol 1968; 28: 1712-1718. Rizkallah T, Gurpide E, Vandewiele RL. Metabolism of hCG in man. J Clin Endocrinol 1969; 29: 92-100. Lahteenmaki P. The disappearance of hCG and return of pituitary function after abortion. Clin Endocrinol 1978; 101-l 12: 1978.
24
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29
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31 32
Marrs RP, Kletzky OA, Howard WF, Mishell DR. Disappearance of human chorionic gonadotropin and resumption of ovulation following abortion. Am J Obstet Gynecol 1979; 135: 731-736. Steier JA, Bergsjo P, Myking OL. Human chorionic gonadotropin in maternal plasma after induced abortion, spontaneous abortion and removed ectopic pregnancy. Obstet Gynecol 1984; 64: 391-394. Holtz G. Human chorionic gonadotropin regression following conservative surgical management of tubal pregnancy. Am J Obstet Gynecol 1983; 147: 347-348. Kamrava MM, Taymor ML, Berger MJ, Thompson IE, Seibel MM. Disappearance of human chorionic gonadotropin following removal of ectopic pregnancy. Obstet Gynecol 1983; 62: 486-488. Kontoravdis A, Kassanos D, Chryssicopoulos I, SouchleriPhocas I, Kilbassanis H. hCG regression after treatment in active and regressed extrauterine pregnancies. Eur J Obstet Gynecol Reprod Biol 1987; 26: 225-231. La Sala GB, Torelli MG, Pagliani A, Borasi G, Dotti C. Human chorionic gonadotropin regression following removal of ectopic pregnancy. Acta Eur Fertil 1987; 18: 397-401. Pouly JL, Mage G, Gachon F, Gaillard G, Bruhat MA. La decroissance du taux d’HCG apres traitement coelioscopique conservateur de la grossesse extra-uterine. J Gynecol Obstet Biol Reprod 1987; 16: 195-199. Letterie GS, Ramirez EJ. Serum human chorionic gonadotropin surveillance after radical and conservative management of ectopic pregnancy. Int J Fertil 1991; 36: 268-274. Ory SJ, Villanueva AL, Sand PK, Tamura RK. Conservative treatment of ectopic pregnancy with methotrexate. Am J Obstet Gynecol 1986; 154: 1299- 1306. Rodi IA, Sauer MV, Gorrill MJ et al. The medical treatment of unruptured ectopic pregnancy with methotrexate and citrovorum rescue: preliminary experience. Fertil Steril 1986; 46: 81 I-813. Haans LCF, van Kessel PH, Kock HCLV. Treatment of ectopic pregnancy with methotrexate. Eur J Obstet Gynecol Reprod Biol 1987; 24: 63-67. Pansky M, Bukovsky I, Golan A et al. Local methotrexate injection: a nonsurgical treatment of ectopic pregnancy. Am J Obstet Gynecol 1989; 161: 393-396. Kojima E, Abe Y, Morita M, Ito M, Hirakawa S, Momose K. The treatment of unruptured tubal pregnancy with intratubal methotrexate injection under laparoscopic control. Obstet Gynecol 1990; 75: 723-725. Kooi S, Kock HCLV. Treatment of tubal pregnancy by local injection of methotrexate after adrenaline injection into the mesosalpinx: a report of 25 patients. Fertil Steril 1990; 54: 580-584. Mtnard A, Crequat J, Mandelbrot L, Hauuy J-P, Madelenat P. Treatment of unruptured tubal pregnancy by local injection of methotrexate under transvaginal sonographic control. Fertil Steril 1990; 54: 47-50. Kooi GS. Methotrexate: a nonsurgical treatment of tubal pregnancy. Ph.D. Thesis 1991, State University, Utrecht. Stovall TG, Ling FW, Gray LA, Carson SA, Buster JE. Methotrexate treatment of unruptured ectopic pregnancy: a report of 100 cases. Obstet Gynecol 1991; 77: 749-753. Egarter C, Husslein P. Treatment of ectopic pregnancy by means of prostaglandins. Prostaglandins Leukot Essent Fatty Acids 1989; 35: 91-92. Husslein P, Fitz R, Pateisky N, Egarter E. Prostaglandin injection for termination of tubal pregnancy: preliminary results. Am J Perinatol 1989; 6: 117-120. Vejtorp M, Vejerslev LO, Ruge S. Local prostaglandin treatment of ectopic pregnancy. Hum Reprod 1989; 4: 464-467. Lindblom B, Hahlin M, Lundorff P, Thorburn J. Treatment of
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64
33
34
35
36
tubal pregnancy by laparoscope-guided injection of prostaglandin FZalpha. Fertil Steril 1990; 54: 404-408. Dericks-Tan JSE, Scholz C, Taubert H-D. Spontaneous recovery of ectopic pregnancy: a preliminary report. Em J Obstet Gynecol Reprod Biol 1987; 25: 181-185. Garcia AJ, Aubert JM, Sama J, Josimovich JB. Expectant management of presumed ectopic pregnancies. Fertil Steril 1987; 48: 395-400. Fernandez H, Rainhorn JD, Papiernik E, Bellet D, Frydman R. Spontaneous resolution of ectopic pregnancy. Obstet Gynecol 1988; 71: 171-174. Budowick M, Johnson TRB Jr, Genadry R, Parmley TH, Woodruff JD. The histopathology of the developing tubal ectopic pregnancy. Fertil Steril 1980; 34: 169-171.
37 38 39
40
Stock RJ. Histopathologic changes in tubal pregnancy. J Reprod Med 1985; 30: 923-928. Parmley TH. The histopathology of tubal pregnancy. Clin Obstet Gynecol 1987; 30: 119-128. Senterman M, Jibodh R, Tulandi T. Histopathologic study of ampullary and isthmic tubal ectopic pregnancy. Am J Obstet Gynecol 1988; 159: 939-941. Vermesh M, Silva PD. Rosen GE, Stein AL, Fossum GT, Sauer MV. Management of unruptured ectopic gestation by linear salpingostomy: a prospective randomised clinical trial of laparoscopy versus laparotomy. Obstet Gynecol 1989; 73: 400-404.
Serum hCG decline following salpingotomy or salpingectomy for extrauterine pregnancy P. Hellemans, J. Gerris*, M. Joostens, S. van der Meer, P. Verdonk, M. Francx Department
of Obstetrics. Gynecology and Fertility,
Middelheim
Hospital.
Lindendreef
I, B-2020 Antwerp, Belgium
(Accepted 30 September 1993)
Abstract Twenty-five women with ectopic pregnancy were surgically treated, fifteen by conservative salpingotomy and ten by radical salpingectomy. All patients showed a clinically normal postoperative course. Serum human chorionic gonadotropin (hCG) levels were determined serially before and after the surgical procedure until non-pregnant values (< 5 mI.U./ml) were reached. Serum hCG decline was compared between patients treated by salpingotomy versus salpingectomy, using calculated hCG half-life times. We observed a significantly slower decline of serum hCG levels during the early phase of hCG disappearance in patients treated by salpingotomy versus patients treated by salpingectomy. Key
words:
Ectopic
pregnancy;
Salpingectomy;
Salpingotomy;
1. Introduction During the last two decades, the management of ectopic pregnancy has undergone major developments. Because of the availability of improved diagnostic techniques, the typical clinical situation of severe hemorrhagic shock due to hemoperitoneum entailing immediate laparotomy has been gradually replaced by well-planned, often laparoscopic, surgery allowing conservative management of the tubes and ovaries [l-4]. However, the use of these conservative techniques has given rise to the risk of the so-called persistent ectopic pregnancy. Persistent ectopic pregnancy can be defined as a pathological entity, caused by the continual growth of trophoblastic tissue, requiring additional treatment after initial conservative management [5-71. In order to diagnose this pathological condition postoperatively, monitoring of serum human chorionic gonadotropin (hCG) has become an integral part of the follow-up treatment of women who suffer an ectopic pregnancy and are treated either surgically or medically [2,3,6,8]. The disappearance curves and times of hCG from the
* Corresponding 0028-2243/94/$07.00 SSDI
author.
0
0028-2243(93)01709-3
1994
Elsevier
Science Ireland
Serum hCG half-life time
plasma have been studied after delivery [9], after intravenous administration [lo], after spontaneous and induced abortion [ 1l- 131, after removal of ectopic pregnancy [6,13- 191 and after second-trimester hysterectomy [12]. These studies have shown a positive correlation between initial preoperative serum hCGlevels and the disappearance time [9,12,13,15,18,19]. However, these studies did not agree with respect to the length of the hCG half-life times and the possible correlation between the initial serum hCG value and the hCG half-life [9,14,17,18]. All authors who studied the metabolism of hCG in man agree on the biphasic pattern of its regression curve, consisting of a fast initial component in the first 24-48 h, followed by a slow component [9,10,14,15,17]. Several authors described hCG disappearance from plasma following systemic or local methotrexate treatment [20-281, following local prostaglandin treatment [29-321 and during expectant management [33-351 as non-surgical treatment modalities for ectopic pregnancy. Globally, much slower hCG disappearances are being observed following nonsurgical approach compared with surgical management. Histopathologic observations of developing tubal ectopic pregnancies have shown that the trophoblastic tissue rapidly invades the lamina propria and the
Ltd. All rights reserved.
P. Hellemans et al. /Eur. J. Obstet. Gynecol. Reprod. Biol. 53 (1994) 59-64
60
muscularis of the tube and begins to grow at an extratubal but still retroperitoneal site [36]. In another study invasiveness of the trophoblast appeared to be limited to the lamina propria and tubal rupture was proposed to be secondary to localized distension and vascular compromise with hemorrhagic necrosis [37]. The invading character of the developing trophoblast and its aggressiveness towards the muscularis of the tube appears to be related to the location of the ectopic gestation, i.e. ampullary or isthmic [38,39]. Taking into account the above mentioned histopathologic considerations, one could easily imagine small amounts of viable trophoblastic tissue staying behind in the wall of the fallopian tube after successful surgical approach. These small amounts of residual active trophoblast could theoretically continue to produce hCG before finally degenerating. This could cause a delay in hCG clearance, resulting in higher hCG half-life times when compared with situations where a more radical surgery is performed and all trophoblastic tissue completely removed. The aim of our study is to compare serum hCG clearance in women undergoing radical salpingectomy versus technically complete salpingotomy for extrauterine pregnancy, taking into account the different components of the hCG disappearance curve in man. 2. Materials and methods Twenty-five patients with a preoperative diagnosis of ectopic pregnancy underwent surgical treatment: ten were treated by salpingectomy, three laparoscopically and seven through laparotomy, and fifteen were treated by salpingotomy, nine laparoscopically and six through laparotomy. Salpingotomy was performed using CO? laser equipment (Oplimas, Carl Zeiss, Germany), followed by trophoblast extraction, extensive washing of the tubal cavity and aspiration of the extracted trophoblastic tissue. The decision whether conservative or radical surgery was carried out was based on the presence and severity of hemoperitoneum, the physician’s experience with operative videolaparoscopy and microsurgical procedures, the tuboperitoneal status and, finally, previous history of ectopic gestation in the affected fallopian tube. In all patients uterine curettage was performed at the same time. In all patients serial quantitative serum hCG determinations were carried out immediately preoperatively, 24 h postoperatively, 48 h postoperatively and from then on every 4 days until serum hCG levels reached nonpregnant values (< 5 mI.U./ml). In all patients half-life times for serum hCG were calculated by the expression [9]: 0.693
TN = ~
r
where r=
log cont. at time a - log cont. at time b 0.434 x time interval
In each patient, the half-life time for serum hCG was calculated for the complete postoperative follow-up period until serum hCG reached non-pregnant values, and separately for the first 48 h postoperatively (initial phase - fast component) and for the time interval between 48 h postoperatively and the moment serum hCG level reached non-pregnant values (~5 mI.U./ml) (late phase - slow component). We compared the calculated half-life times for the above defined time intervals between the women treated by salpingectomy versus those treated by salpingotomy. To evaluate the effect of the height of the initial serum hCG level on hCG half-life time we compared in both the salpingectomy group and in the salpingotomy group, the calculated half-life time in women with an initial serum hCG level >2000 mI.U./ml with the calculated half-life time in women with an initial hCG level <2000 mI.U./ml for all three previously defined time intervals of the follow-up period. Serum hCG determinations were carried out on sera freshly separated from peripheral blood. We used a commercial kit for the radioimmunological determination of @-hCG subunit (RIA-gnost hCG, Behringwerke AG, Marburg, Germany) based on the principle of a sandwich assay using monoclonal mouse anti-&hCG ( ‘251-labelled) antibody and solid phase monoclonal mouse anti-&hCG antibody. RIA-gnost hCG has been standardized against the first IRP WHO (75/537) in mI.U./ml. Statistical analysis was carried out using Wilcoxon signed ranks test for non-parametric values. 3. Results All patients showed normal postoperative courses and no case of persistent ectopic pregnancy was observed in the conservatively treated group. No chorionic villi were observed in any of the endometrial contents presented for pathological examination. In all patients the diagnosis of ectopic pregnancy was confirmed by pathologic examination of the removed fallopian tube following salpingectomy or removed tubal contents following salpingotomy. Initial hCG level (mean f S.E.M.) in the salpingotomy group and in the salpingectomy group were 2281 f 442 mI.U./ml (n = 15) and 4498 f 1803 mI.U./ml (RIO), respectively, which are statistically comparable values (P > 0.10). Initial hCG levels from both groups are shown in Table 1. In both treatment groups, hCG half-life times during
61
P. Hellemans et al. /Eur. J. Obsret. Gynecol. Reprod. Biol. 53 (1994) 59-64 Table 1 Initial hCG levels (mI.U./ml) from the salpingotomy and from the salpingectomy group (n = IO) Salpingotomy
Salpingectomy
2500 4230 2150 6980 2560 2140 2960 3170 1470 35 1920 1400 I800 784
2270 3370 I7 600 10700 7010 2620 1850 868 232 813
group
(n = 15)
II0
the early phase of hCG disappearance were significantly shorter than during the late phase: 26.9 + 6.1 h vs. 62.1 f 12.1 h in the salpingotomy group (P = 0.0019) and 15 f 1.7 h vs. 52.8 f 5.3 h in the salpingectomy group (P = 0.012). We did not find a statistically significant difference in serum hCG half-life times between patients treated by
salpingectomy versus patients treated by salpingotomy for the total follow-up period (early and late phase taken together) (P = 0.51) and for the late phase (P = 0.57). However, for the early phase, hCG half-life time was significantly longer in the salpingotomy group than in the salpingectomy group: 26.9 f 6.1 h vs. 15 f 1.7 h (P = 0.04), respectively (Fig. 1). The level of the initial serum hCG value (>2000 mI.U./ml as compared with ~2000 mI.U./ml) did not appear to influence the course of hCG disappearance in either treatment group (salpingotomy or salpingectomy) in either of the previously defined time intervals (Fig. 1). Disappearance curves for serum hCG in both treatment groups are depicted in Fig. 2. One patient treated by laparoscopic lasersalpingotomy for a left-sided preampullary ectopic gestation and having an initial hCG level of 2500 mI.U./ml showed a very slow hCG decline during the late phase of hCG regression with a half-life time of 212 h. Another patient treated by laparoscopic lasersalpingotomy with an initial hCG level of 2150 mI.U./ml showed a very slow decline over the early phase of hCG regression with a half-life time of 102 h. Both patients showed normal postoperative courses. The data on these two patients were also included in the statistical comparisons.
% of titer
t1
2 80
bun)
6.
@
;i
tl 2
Ihours) @
81 60
4.
0
I
I
I
40
72
96
I
120
I
144
168
192
216
hours postoperative
20 0
t1 2
I
24
% of titer
*O 60
‘4
(hours)4. 0
20 0
a ~~0.05
q EarlyPhase qLatePhase
Fig. I. Histogrammatic representation of hCG half-life times (mean f S.E.M.): A Salpingotomy (left) versus salpingectomy (right), for the early phase (P = 0.04), the late phase (P = 0.57) and the total phase (P = 0.51). B Salpingotomy group: initial hCG >2000 mI.U./ml (left) versus <2000 mI.U./ml (right) for early phase (P = 0.35), late phase (P = 0.50) and total phase (P = 0.22). C Salpingectomy group: initial hCG >2000 mI.U./ml (left) versus < 2000 mI.U./ml (right) for early phase (P = 0.71). late phase (P = I) and total phase (P = 0.29).
24
48
72
96
120
144
168
192
216
hours postoperative
Fig. 2. Percentage of preoperative hCG concentration remaining atter surgical procedure in the salpingotomy group (n = 15) (upper pannel) and in the salpingectomy group (n = IO) (lower pannel).
62
P. Hellemans et al. /Eur. J. Ohsret. Gynecol. Reprod. Biol. 53 (19941 59-64
4. Discussion
The disappearance of hCG from the bloodstream after termination of pregnancy, whether intrauterine or extrauterine, is initially a rapid exponential decline with a half-life of hCG between 5 and 13 h, followed by a slower continually decreasing rate of between 22 and 52 h [9,10,14,15,17]. Holtz [14] described P-hCG clearance following salpingotomy for ectopic gestation in three patients by plotting to a percentage of the initial titer converted, postoperative &hCG values versus time from operation. Half-life values for sequential 24-h intervals after operation were 12.9, 19.4 and 51.7 h, respectively. La Sala et al. [ 171investigated hCG decline in 41 women undergoing salpingectomy for ectopic gestation. They described hCG clearance by a biexponential model and concluded their observations to be similar to the observations by Pouly et al. [ 181following laparoscopic conservative surgical management. Pouly et al. [18] studied the drop in hCG levels in 76 patients following laparoscopic conservative surgical management for ectopic gestation and presented a nomogram for the postoperative follow-up after laparoscopic treatment for ectopic pregnancy relying on the hCG clearance rate. They observed a hCG half-life time of 19.4 h in the first 48 postoperative hours and a half-life time of 63.9 h in the subsequent days. They stated the observed drop in hCG after conservative treatment using laparoscopy is similar to the one known to occur after conservative treatment using laparotomy. Steier et al. [13] studied 35 cases of ectopic pregnancy treated by laparotomy. They also observed a biphasic hCG regression pattern, but did not specify whether salpingotomy or salpingectomy was performed. Kamrava et al. [ 151 studied the length of time serum hCG remains detectable following removal of ectopic pregnancy in a group of seven women who underwent salpingectomy or partial resection of the involved fallopian tube and in a group of nine women who underwent salpingotomy or Iimbrial expression. They concluded the initial titer of hCG to be a significant factor in determining the length of time it remains postoperatively detectable in the serum. They also observed a biphasic regression pattern in both study groups with an initial fast component followed by a slow component. Despite the fact that hCG regression curves in both groups seem very comparable, no comparison on a statistical basis was carried out in this study [15]. Kontoravdis et al. [16] studied the regression of hCG levels in nine patients undergoing salpingectomy for active tubal pregnancy and six patients undergoing salpingotomy for regressed tubal pregnancies. Mean hCG values in both groups showed the same exponential regression pattern but mean values of the hormone in both groups showed significant differences during the whole observed time interval. Letterie
and Ramirez [19] studied the clearance time for serum hCG in ectopic pregnancy by monitoring the interval between surgical intervention and complete disappearance of hCG in 15 patients with ruptured tubal ectopic pregnancy managed by salpingectomy and in 10 patients with unruptured, ectopic pregnancy managed by salpingotomy. Mean initial serum hCG levels differed significantly between both groups. Higher initial serum hCG levels were observed in the salpingectomy group. They concluded duration of clearance to be correlated primarily to the initial hCG concentration. This explains the slower hCG clearance observed in the salpingectomy group. They also presented a nomogram for postoperative hCG surveillance following salpingotomy. In a prospective randomized clinical trial comparing management of unruptured ectopic gestation by linear salpingotomy following laparotomy versus laparoscopy, a similar &hCG regression pattern in both study groups was observed [40]. In our study we compared 15 patients successfully treated by salpingotomy for ectopic gestation with 10 patients treated by salpingectomy. All patients showed normal postoperative courses and no case of persistent ectopic pregnancy was observed in the conservatively treated group. We calculated half-life times for different time intervals, i.e. early phase, late phase and total follow-up period. In both study groups we observed hCG clearance consists of more than one component, i.e. a fast component followed by a slow component, as previously shown by different authors [9,10,14,15,17,18]. Initial serum hCG levels did not appear to be a determining factor for hCG half-life time. We did not find a significant difference in P-hCG half-life times between women in the salpingectomy group and women in the salpingotomy group during the late phase and the total follow-up period. However, a significant difference was found in the early phase, where a slower hCG regression pattern was observed in the salpingotomy group. Several authors have declared postoperative hCG regression patterns to be similar in women undergoing tube-conserving surgery (salpingotomy, fimbrial expression), compared with women undergoing radical surgery (salpingectomy, segmental resection) for ectopic pregnancy [15-171. However, by taking into account the biphasic pattern of the hCG regression curve in man in our statistical comparisons, we demonstrated a significantly slower hCG decline following salpingotomy versus salpingectomy for ectopic gestation in the first 48 postoperative hours. This could be explained by the postoperative persistence of small amounts of residual viable trophoblastic tissue in the tubal wall following conservative surgery. This residual trophoblastic tissue could be held responsible for ongoing hCG production before secondarily degenerating, resulting in a higher hCG half-life time in the early postoperative period.
P. ffeffemans
et al. /Eur.
63
J. Obsfet. Gynecol. Reprod. Biol. 53 (1994) 59-64
When considering our observations, this purely theoretical reasoning seems applicable only to the early phase of hCG disappearance but not to the total follow-up period and to the late phase of hCG disappearance. Two patients treated by salpingotomy showed much longer hCG half-life times compared with the other patients. This also could be due to incomplete removal of
12
trophoblastic tissue at surgical intervention, responsible for ongoing hCG production and higher half-life times before finally degenerating. The observed phenomenon should be discriminated from the so-called persistent ectopic pregnancy, a pathological entity caused by the continual growth of trophoblastic tissue, requiring additional treatment after initial conservative management. No case of persistent ectopic pregnancy was observed in our study group. A study by Vermesh et al. [6] showed that early detection of persistent ectopic pregnancy following conservative surgical management, relying on postoperative progesterone and beta-hCG surveillance, is only possible from the sixth postoperative day onwards. From our observations we conclude hCG clearance to be significantly slower in the first 48 postoperative hours following successful salpingotomy, compared with salpingectomy for ectopic gestation. This observation could be explained by the postoperative persistence of secondarily degenerating, viable trophoblastic tissue in the wall of the fallopian tube in the early postoperative period following conservative surgical management.
14
13
15
16
17
18
19
20
21
22
5. References 23 1 2 3 4 5
6
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Stock RJ. Histopathologic changes in tubal pregnancy. J Reprod Med 1985; 30: 923-928. Parmley TH. The histopathology of tubal pregnancy. Clin Obstet Gynecol 1987; 30: 119-128. Senterman M, Jibodh R, Tulandi T. Histopathologic study of ampullary and isthmic tubal ectopic pregnancy. Am J Obstet Gynecol 1988; 159: 939-941. Vermesh M, Silva PD. Rosen GE, Stein AL, Fossum GT, Sauer MV. Management of unruptured ectopic gestation by linear salpingostomy: a prospective randomised clinical trial of laparoscopy versus laparotomy. Obstet Gynecol 1989; 73: 400-404.