56 6 Brule AJC, van den Snijders PJF, Gordijn RLJ et al. General primer mediated polymerase chain reaction permits the detection of sequenced and still unsequenced human papillomavirus genotypes in cervical scrapes and carcinomas. Int J Cancer: 1990;45:644-649. Beckmann AM, Kiviat NB, Daling JR, Sherman KJ, McDougall JK. Human papilloma virus type 16 in multifocal neoplasia of the femal genital tract. Int J Gynaecol Path01 1988;7:39-47. Walboomers JMM, Melchers WJG, Mullink H et al. Sensitivitiy of in situ detection with biotinylated probes of human papilloma virus type 16 DNA in frozen tissue sections of squamous cell carcinomas of the cervix. Am J Path 1988;181:587-594. Mullink H, Vos W, Jiwa M, Horstman A, Valk P. van der Walboomers JMM, Meijer CJLM. Application and comparison of silver intensification methods for the di-
aminobenzidine and diaminobenzidine nickel endproduct of the peroxidation reaction in immunohistochemistry and in situ hybridization. J Histochem Cytochem 1991; in press. 10 Spradbow PB. Immune response to papillomavirus infection. In: SyrjHnen K, Gissmann L, Koss LG, eds. Papillomaviruses and human disease. Heidelberg: Springer-Verlag 1987;334-378. 11 Ho L, Chow V, Shong T, Tay SK, Villa LL, Bernhard HU. Sequence variants of human papillomavirus type 16 in clinical samples permit verification and extension of epidemiological studies and construction of a phytogenetic tree. J Clin Microbial 1991;29:1765-1772. 12 Nipro JM, Baker SJ, Preisinger AC, Jessup JM, Hostettet R, Cleary K, Bigner SH, Davidson N, Berglin S, Devilee P, Glover T, Collins FS, Weston A, Modali R, Harris CC, Vogelstein B. Mutations in the p.53 gene occur in diverse human tumour types. Nature 1989;342:705-708.
* * *
European Journal of Obstetrics & Gynecology and Reproductive Biology, 46 (1992) 56-59 Q 1992 Elsevier Science Publishers B.V. All rights reserved 0028-2243/92/$05.00 EUROBS 01334
Tubal rupture despite low and declining serum hCG levels Sjarlot Kooi a, Hans C.L.V. Kock a and Frans H.P.M. van Etten b a Department of Gynaecology and Obstetrics and b Depaflment of Pathology, Maria and Elisabeth Hospital, Tilburg, Netherlands Accepted for publication 9 December 1991 Human chorionic gonadotropin; Tubal rupture; Ectopic pregnancy
Introduction Serial serum assays for the nadotropin (hCG) concentration
human
chorionic
go-
are widely accepted
Correspondence to: Dr. H.C.L.V. Kock, Maria Hospital, Dept. Gynaecology and Obstetrics, Tilburg, The Netherlands. ’ First International Reference Preparation (IRP). 2 Abott 50 IU (Urine test). 3 Pregnosticon 500 IU.
for the diagnosis and treatment of suspected ectopic pregnancy. In conservative treatment of ectopic pregnancies, the determination of the serum hCG concentration is mandatory [l]. The clinical implication of a decrease in serum hCG is, however, not clear [2-41. It is suggested that patients with an unruptured tubal pregnancy and declining serum hCG concentrations can safely be managed by observation [1,5]. Especially those patients that have a combination of low initial and declining serum hCG concentrations run a very low risk of tubal rupture [6]. In most case reports these patients recover spontaneously [7,8].
51 TUBAL RUPTURE DESPITE A VERY LOW AND A DECLINING hCG CONCENTRATION DURINQ OBSERVATIVE MANAQEMENT hCG mlU/mL 1000 3
(IRP)
TUBALRUPTURE LAPAROTOMY
0
2
4
6
8
10
12
14
16
18
20
22
DAYS
Fig. 1. hCG disappearance curve after observative management of tubal pregnancy. hCG expressed in terms of first IRP.
Readmission followed 2 weeks after discharge due to increasing discomfort in the right lower abdominal quadrant. Transvaginal ultrasonic scanning revealed a large irregular mass on the right side of the uterus and free fluid in the cul de sac. At laparotomy there was a ruptured serosa of the ampullary part of the tube and an estimated intraperitoneal blood loss of 400 cc. A salpingectomy was performed. A blood sample taken right before surgical intervention had a serum hCG concentration of 23.7 mIU/ml (Fig. 1). At gross inspection much of the observed tubal distention was due to a fresh intraluminal bloodclot. At histology placental villi were seen. The tubal wall showed fibrinous inflammatory changes in all three coats of the tube. On the serosal side there was a fibrinous inflammatory reaction (Fig. 2). Comment
The case presented
is well documented
and demon-
strates that, in spite of low concentrations of hCG ’ and the fact that all parameters related to the risk of tubal rupture were favourable, tubal rupture can occur. Case report
A 26-year-old, gravida 1, para 0, with a last menstrual period on 20 Januari 1988, was admitted on 15 February 1988, with a 2-weeks history of increasing right lower quadrant pain, vaginal spotting and a positive urine pregnancy test (50 IU) *. Gynecologic history revealed subfertility during 2 years, no former use of an intra-uterine device nor pelvic inflammatory disease. Examination of the abdomen demonstrated moderate pain over the right lower abdominal quadrant but no rebound tenderness. On inspection there was mild bleeding from a closed external ostium uteri. The uterus was slightly enlarged with tenderness over a normal right adnexa. An urine slide-test (500 IU) 3 was negative. Transvaginal ultrasonic scanning revealed an empty uterus, no adnexal mass nor free fluid in the cul de sac. The patient was admitted for observation. Serum hCG concentrations were determined at 2day intervals. The initial serum hCG was 167 mIU/ml and the hCG-curve decreased over the first days. The patient’s discomfort ceased. Repeat ultrasonic scanning revealed no abnormalities. The patient agreed with observant management as an out patient. She was instructed on possible signs of tubal rupture. At the time of discharge her serum hCG concentration was 125 mIU/mL. The hCG values, tested every other day, declined until they were 30 mIU/ml 10 days later.
Romero et al. studied the hCG concentrations before surgery in 50 patients with a surgically verified ectopic pregnancy. They reported that 49% had falling hCG concentrations between the 2-5 day sampling intervals [9]. The natural course of ectopic pregnancies with falling hCG-concentrations is unknown. Sauer et al. treated 26 patients with unruptured tubal pregnancies either by MTX or observation. The treatment modality was biased and based upon initial levels of hCG and their decline. The five patients with a serum hCG decline < 15% over 48 h were managed by observation and all had uneventful clinical courses [lo]. From other studies that observed tubal pregnancies with decreasing serum hCG concentrations it was concluded that surgical intervention proved necessary in a percentage ranging from 0 to 20% Ill]. It is remarkable that all reported tubal pregnancies that ruptured during methotrexate treatment did so at the time of decreasing serum hCG concentrations [12141. The maximum time interval between MTX therapy and the moment of tubal rupture was 23 days [lo]. Hence a decrease in serum hCG is certainIy no guarantee against tubal rupture. The serum hCG-disappearance curves, obtained after radical surgery, show the biologic half-life value or elimination curve of serum hCG [1.5]. A hCG-disappearance curve with a longer half-life value, points to a decreasing total number of chorionic cells but does not rule out the simultaneous proliferation of trophoblasts 116,171.This proliferation of trophoblasts in the salpinx can be harmful and might cause tubal rupture. The ideal therapy would result in an immediate elimination of all trophoblastic cells. This would manifest itself by
58
Fig. 2. Histology of the ruptured tube with a serum hCG of 23.7 mIU/ml. Haematoxilin & Eosin staining. Magnification: 50 X Tubal wall with intraluminar bloodcloth (fresh) surrounded by viable and non-viable trophoblastic villi.
a hCG-disappearance curve as seen after radical surgery. At this moment there is no conservative treatment that induces this rapid hCG-fall, and therefore any conservative treatment has the risk of ongoing tubal invasion, destruction and rupture. The main problem in clinical management is the absence of a good parameter that predicts tubal rupture. Initial serum hCG concentration, fetal heart-motion on ultrasound, and also treatment modality are related to tubal rupture. This is not so for such factors as tubal diameter (although often used as inclusion criterium) and pregnancy duration [18]. The compiled data of observative management and medical treatment show a tendency that patients with higher initial serum hCG concentrations are at greater risk of tubal rupture than patients with lower initial serum hCG concentrations [III. Our case clearly demonstrates that even patients with very low initial and declining serum hCG concentrations are at risk for tubal rupture. Therefore careful surveillance and patient instruction is needed. In conclusion, tuba1 rupture can occur both during observation and conservative treatment as illustrated by our case. A reliable parameter to predict the risk of tubal rupture for the individual patient is unknown, although studies on human placental lactogen, the free a-subunit of hCG, the ratio of hCG (Y-and P-subunits and ultrasonic placenta1 flow studies might give a clue to this problem [19-221. Until the time that impending tubal rupture can be judged trom a reliable parameter, conservative management is only safe under good surveillance and patient instruction, even in patients with very low and declining serum hCG concentrations.
References 1 Leach RE, Ory SJ. Modern management ofectopic pregnancy. J Reprod Med 1989;34:324-337. 2 Pittaway DE. P-hCG in ectopic pregnancy. Clin Obstet Gynecol 1987;30:129-135. 3 Hussa RO. Human chorionic gonadotropin, a clinical marker: review of its biosynthesis. Ligand Rev 3 1981;(suppl 211-44. 4 Patillo RA, Hussa RO, Yorde DE, Cole LA. Hormone synthesis by normal and neoplastic human trophoblast. In: Loke and Whyte eds. Biology of trophoblast. Amsterdam: Elsevier Science Publishers, 283-316;1983. 5 Tulandi T, Bret PM, Atri M, Senterman M. Treatment of ectopic pregnancy by transvaginal untratubal methotrexate administration. Obstet Gynecol 1991;77:627-630. 6 Gretz E, Quagliarello J. Declining serum concentrations of the P-subunit of human chorionic gonadotropin and ruptured ectopic pregnancy. Am J Obstet Gynecol 1987;156:940-941. 7 Fernandez H, Rainhorn JD, Papiernik E et al. Spontaneous resolution of ectopic pregnancy. Obstet Gynecol 1988;71:171-175. 8 Garcia AJ, Aubert JM, Sama J, Josimovich JB. Expectant management of presumed ectopic pregnancies. Fertil Steril 1987;48:395-399. 9 Romero R, Kadar N, Cope1 JA et al. The value of serial human chorionic gonadotropin testing as a diagnostic tool in ectopic pregnancy. Am J Obstet Gynecol 1986;155:392394. 10 Sauer MV, Gorill MJ, Rodi IA et al. Nonsurgical management of unruptured pregnancy: an extended clinical trial. Fertil Steril 1987;48:752-753. 11 Kooi S, Kock HCLV. A review of the literature on nonsurgical treatment in tubal pregnancies. Survey Obstet Gynecol 1991; in press.
59 12 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. 13 Stovall TG, Ling FW, Buster JE. Outpatient chemotherapy of unruptured ectopic pregnancy. Fertil Steril 1989; 51:435-438. 14 Ory SI, Villanueva AL, Sand PH, Tamura RK. Conservative treatment of ectopic pregnancy with Methotrexate. Am J Obstet Gynecol 1986;154:1299-1306. 15 Holtz G. Human chorionic gonadotropin regression following conservative surgical management of tubal pregnancy. Am J Obstet Gynecol 1983;47:347-348. 16 Braunstein GD, Grodin JM, Vaitukaitis J, Ross GT. Secretory rates of human chorionic gonadotropin by normal trophoblast. Am J Obstet Gynecol 1973;115:447-450. 17 Koide Y, Aoki T, Hreshchymshyn MM. Effects of hor-
18
19
20
21
22
mones, methotrexate and dactinomycin on benign trophoblast. Am J Obstet Gynecol 1971;109:453-456. Cartwright PS, Moore RA, Dao AH et al. Serum hCG levels relate poorly to the size of tubal pregnancy. Fertil Steril 1987;48:679-671. L’Hermite-Baleriaux AM, Exter C van, Delville JL. Alteration of free hCG subunits secretions in ectopic pregnancy. Acta Endocrinol 1982;100:109-117. Stabile I, Grudzinskas G. Ectopic pregnancy: a review of incidence, etiology and diagnostics aspects. Obstet Gynecol Survey 1990;45:335-347. Letterlie GS, Hay DL. Secretions of intact chorionic gonadotropin (hCG) and its P-subunit in three events of pregnancy. Fertil Steril 199O;P230, S161. Taylor KJW, Meyer WR. New Techniques in the diagnosis of ectopic pregnancy. Obstet Gynecol Clin North Am 1991;18:39-54.
aminobenzidine and diaminobenzidine nickel endproduct of the peroxidation reaction in immunohistochemistry and in situ hybridization. J Histochem Cytochem 1991; in press. 10 Spradbow PB. Immune response to papillomavirus infection. In: SyrjHnen K, Gissmann L, Koss LG, eds. Papillomaviruses and human disease. Heidelberg: Springer-Verlag 1987;334-378. 11 Ho L, Chow V, Shong T, Tay SK, Villa LL, Bernhard HU. Sequence variants of human papillomavirus type 16 in clinical samples permit verification and extension of epidemiological studies and construction of a phytogenetic tree. J Clin Microbial 1991;29:1765-1772. 12 Nipro JM, Baker SJ, Preisinger AC, Jessup JM, Hostettet R, Cleary K, Bigner SH, Davidson N, Berglin S, Devilee P, Glover T, Collins FS, Weston A, Modali R, Harris CC, Vogelstein B. Mutations in the p.53 gene occur in diverse human tumour types. Nature 1989;342:705-708.
* * *
European Journal of Obstetrics & Gynecology and Reproductive Biology, 46 (1992) 56-59 Q 1992 Elsevier Science Publishers B.V. All rights reserved 0028-2243/92/$05.00 EUROBS 01334
Tubal rupture despite low and declining serum hCG levels Sjarlot Kooi a, Hans C.L.V. Kock a and Frans H.P.M. van Etten b a Department of Gynaecology and Obstetrics and b Depaflment of Pathology, Maria and Elisabeth Hospital, Tilburg, Netherlands Accepted for publication 9 December 1991 Human chorionic gonadotropin; Tubal rupture; Ectopic pregnancy
Introduction Serial serum assays for the nadotropin (hCG) concentration
human
chorionic
go-
are widely accepted
Correspondence to: Dr. H.C.L.V. Kock, Maria Hospital, Dept. Gynaecology and Obstetrics, Tilburg, The Netherlands. ’ First International Reference Preparation (IRP). 2 Abott 50 IU (Urine test). 3 Pregnosticon 500 IU.
for the diagnosis and treatment of suspected ectopic pregnancy. In conservative treatment of ectopic pregnancies, the determination of the serum hCG concentration is mandatory [l]. The clinical implication of a decrease in serum hCG is, however, not clear [2-41. It is suggested that patients with an unruptured tubal pregnancy and declining serum hCG concentrations can safely be managed by observation [1,5]. Especially those patients that have a combination of low initial and declining serum hCG concentrations run a very low risk of tubal rupture [6]. In most case reports these patients recover spontaneously [7,8].
51 TUBAL RUPTURE DESPITE A VERY LOW AND A DECLINING hCG CONCENTRATION DURINQ OBSERVATIVE MANAQEMENT hCG mlU/mL 1000 3
(IRP)
TUBALRUPTURE LAPAROTOMY
0
2
4
6
8
10
12
14
16
18
20
22
DAYS
Fig. 1. hCG disappearance curve after observative management of tubal pregnancy. hCG expressed in terms of first IRP.
Readmission followed 2 weeks after discharge due to increasing discomfort in the right lower abdominal quadrant. Transvaginal ultrasonic scanning revealed a large irregular mass on the right side of the uterus and free fluid in the cul de sac. At laparotomy there was a ruptured serosa of the ampullary part of the tube and an estimated intraperitoneal blood loss of 400 cc. A salpingectomy was performed. A blood sample taken right before surgical intervention had a serum hCG concentration of 23.7 mIU/ml (Fig. 1). At gross inspection much of the observed tubal distention was due to a fresh intraluminal bloodclot. At histology placental villi were seen. The tubal wall showed fibrinous inflammatory changes in all three coats of the tube. On the serosal side there was a fibrinous inflammatory reaction (Fig. 2). Comment
The case presented
is well documented
and demon-
strates that, in spite of low concentrations of hCG ’ and the fact that all parameters related to the risk of tubal rupture were favourable, tubal rupture can occur. Case report
A 26-year-old, gravida 1, para 0, with a last menstrual period on 20 Januari 1988, was admitted on 15 February 1988, with a 2-weeks history of increasing right lower quadrant pain, vaginal spotting and a positive urine pregnancy test (50 IU) *. Gynecologic history revealed subfertility during 2 years, no former use of an intra-uterine device nor pelvic inflammatory disease. Examination of the abdomen demonstrated moderate pain over the right lower abdominal quadrant but no rebound tenderness. On inspection there was mild bleeding from a closed external ostium uteri. The uterus was slightly enlarged with tenderness over a normal right adnexa. An urine slide-test (500 IU) 3 was negative. Transvaginal ultrasonic scanning revealed an empty uterus, no adnexal mass nor free fluid in the cul de sac. The patient was admitted for observation. Serum hCG concentrations were determined at 2day intervals. The initial serum hCG was 167 mIU/ml and the hCG-curve decreased over the first days. The patient’s discomfort ceased. Repeat ultrasonic scanning revealed no abnormalities. The patient agreed with observant management as an out patient. She was instructed on possible signs of tubal rupture. At the time of discharge her serum hCG concentration was 125 mIU/mL. The hCG values, tested every other day, declined until they were 30 mIU/ml 10 days later.
Romero et al. studied the hCG concentrations before surgery in 50 patients with a surgically verified ectopic pregnancy. They reported that 49% had falling hCG concentrations between the 2-5 day sampling intervals [9]. The natural course of ectopic pregnancies with falling hCG-concentrations is unknown. Sauer et al. treated 26 patients with unruptured tubal pregnancies either by MTX or observation. The treatment modality was biased and based upon initial levels of hCG and their decline. The five patients with a serum hCG decline < 15% over 48 h were managed by observation and all had uneventful clinical courses [lo]. From other studies that observed tubal pregnancies with decreasing serum hCG concentrations it was concluded that surgical intervention proved necessary in a percentage ranging from 0 to 20% Ill]. It is remarkable that all reported tubal pregnancies that ruptured during methotrexate treatment did so at the time of decreasing serum hCG concentrations [12141. The maximum time interval between MTX therapy and the moment of tubal rupture was 23 days [lo]. Hence a decrease in serum hCG is certainIy no guarantee against tubal rupture. The serum hCG-disappearance curves, obtained after radical surgery, show the biologic half-life value or elimination curve of serum hCG [1.5]. A hCG-disappearance curve with a longer half-life value, points to a decreasing total number of chorionic cells but does not rule out the simultaneous proliferation of trophoblasts 116,171.This proliferation of trophoblasts in the salpinx can be harmful and might cause tubal rupture. The ideal therapy would result in an immediate elimination of all trophoblastic cells. This would manifest itself by
58
Fig. 2. Histology of the ruptured tube with a serum hCG of 23.7 mIU/ml. Haematoxilin & Eosin staining. Magnification: 50 X Tubal wall with intraluminar bloodcloth (fresh) surrounded by viable and non-viable trophoblastic villi.
a hCG-disappearance curve as seen after radical surgery. At this moment there is no conservative treatment that induces this rapid hCG-fall, and therefore any conservative treatment has the risk of ongoing tubal invasion, destruction and rupture. The main problem in clinical management is the absence of a good parameter that predicts tubal rupture. Initial serum hCG concentration, fetal heart-motion on ultrasound, and also treatment modality are related to tubal rupture. This is not so for such factors as tubal diameter (although often used as inclusion criterium) and pregnancy duration [18]. The compiled data of observative management and medical treatment show a tendency that patients with higher initial serum hCG concentrations are at greater risk of tubal rupture than patients with lower initial serum hCG concentrations [III. Our case clearly demonstrates that even patients with very low initial and declining serum hCG concentrations are at risk for tubal rupture. Therefore careful surveillance and patient instruction is needed. In conclusion, tuba1 rupture can occur both during observation and conservative treatment as illustrated by our case. A reliable parameter to predict the risk of tubal rupture for the individual patient is unknown, although studies on human placental lactogen, the free a-subunit of hCG, the ratio of hCG (Y-and P-subunits and ultrasonic placenta1 flow studies might give a clue to this problem [19-221. Until the time that impending tubal rupture can be judged trom a reliable parameter, conservative management is only safe under good surveillance and patient instruction, even in patients with very low and declining serum hCG concentrations.
References 1 Leach RE, Ory SJ. Modern management ofectopic pregnancy. J Reprod Med 1989;34:324-337. 2 Pittaway DE. P-hCG in ectopic pregnancy. Clin Obstet Gynecol 1987;30:129-135. 3 Hussa RO. Human chorionic gonadotropin, a clinical marker: review of its biosynthesis. Ligand Rev 3 1981;(suppl 211-44. 4 Patillo RA, Hussa RO, Yorde DE, Cole LA. Hormone synthesis by normal and neoplastic human trophoblast. In: Loke and Whyte eds. Biology of trophoblast. Amsterdam: Elsevier Science Publishers, 283-316;1983. 5 Tulandi T, Bret PM, Atri M, Senterman M. Treatment of ectopic pregnancy by transvaginal untratubal methotrexate administration. Obstet Gynecol 1991;77:627-630. 6 Gretz E, Quagliarello J. Declining serum concentrations of the P-subunit of human chorionic gonadotropin and ruptured ectopic pregnancy. Am J Obstet Gynecol 1987;156:940-941. 7 Fernandez H, Rainhorn JD, Papiernik E et al. Spontaneous resolution of ectopic pregnancy. Obstet Gynecol 1988;71:171-175. 8 Garcia AJ, Aubert JM, Sama J, Josimovich JB. Expectant management of presumed ectopic pregnancies. Fertil Steril 1987;48:395-399. 9 Romero R, Kadar N, Cope1 JA et al. The value of serial human chorionic gonadotropin testing as a diagnostic tool in ectopic pregnancy. Am J Obstet Gynecol 1986;155:392394. 10 Sauer MV, Gorill MJ, Rodi IA et al. Nonsurgical management of unruptured pregnancy: an extended clinical trial. Fertil Steril 1987;48:752-753. 11 Kooi S, Kock HCLV. A review of the literature on nonsurgical treatment in tubal pregnancies. Survey Obstet Gynecol 1991; in press.
59 12 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. 13 Stovall TG, Ling FW, Buster JE. Outpatient chemotherapy of unruptured ectopic pregnancy. Fertil Steril 1989; 51:435-438. 14 Ory SI, Villanueva AL, Sand PH, Tamura RK. Conservative treatment of ectopic pregnancy with Methotrexate. Am J Obstet Gynecol 1986;154:1299-1306. 15 Holtz G. Human chorionic gonadotropin regression following conservative surgical management of tubal pregnancy. Am J Obstet Gynecol 1983;47:347-348. 16 Braunstein GD, Grodin JM, Vaitukaitis J, Ross GT. Secretory rates of human chorionic gonadotropin by normal trophoblast. Am J Obstet Gynecol 1973;115:447-450. 17 Koide Y, Aoki T, Hreshchymshyn MM. Effects of hor-
18
19
20
21
22
mones, methotrexate and dactinomycin on benign trophoblast. Am J Obstet Gynecol 1971;109:453-456. Cartwright PS, Moore RA, Dao AH et al. Serum hCG levels relate poorly to the size of tubal pregnancy. Fertil Steril 1987;48:679-671. L’Hermite-Baleriaux AM, Exter C van, Delville JL. Alteration of free hCG subunits secretions in ectopic pregnancy. Acta Endocrinol 1982;100:109-117. Stabile I, Grudzinskas G. Ectopic pregnancy: a review of incidence, etiology and diagnostics aspects. Obstet Gynecol Survey 1990;45:335-347. Letterlie GS, Hay DL. Secretions of intact chorionic gonadotropin (hCG) and its P-subunit in three events of pregnancy. Fertil Steril 199O;P230, S161. Taylor KJW, Meyer WR. New Techniques in the diagnosis of ectopic pregnancy. Obstet Gynecol Clin North Am 1991;18:39-54.
