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Methotrexate treatment for ectopic pregnancy after assisted reproductive technology: A case-control study
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GYOBFE-2923; No. of Pages 4 Gyne´cologie Obste´trique & Fertilite´ xxx (2016) xxx–xxx
Available online at
ScienceDirect www.sciencedirect.com
Original article
Methotrexate treatment for ectopic pregnancy after assisted reproductive technology: A case-control study§ Traitement par me´thotrexate des grossesses extra-ute´rines issues d’une assistance me´dicale a` la procre´ation^ A. Ohannessian, P. Crochet, B. Courbiere, A. Gnisci, A. Agostini * Service de gyne´cologie-obste´trique, hoˆpital de La Conception, 147, boulevard Baille, 13005 Marseille, France
A R T I C L E I N F O
A B S T R A C T
Article history: Received 17 February 2016 Accepted 11 April 2016 Available online xxx
Objectives. – Ectopic pregnancy (EP) occurs in 2% to 5.6% of pregnancies achieved by assisted reproductive technology (ART). EP treatment options include medical treatment by uses of methotrexate (MTX) systemic injection. The objective of this study was to compare MTX treatment effectiveness for EP occurring spontaneously or following ART. Methods. – A case-control study performed in the department of obstetrics and gynecology at a tertiary health care center in France. Twenty EP achieved by ART (ART group) and 60 spontaneous EP (SEP group) received MTX treatment between January 2002 and May 2012. The main outcome measures were MTX treatment failure rates, number of MTX injections administered and recovery time. Results. – MTX treatment failure rates observed in ART and SEP groups were similar (3/20 [15%] versus 10/60 [17%]: OR = 0.88 [0.22–3.58]). Mean duration of recovery time in patients with successful MTX treatment did not differ between ART and SEP groups (33 14 days versus 28 13 days, P = 0.39). A second MTX injection was required more frequently in ART group than in SEP group (10/20 [50%] versus 10/60 [17%]: OR = 5 [1.65–15.15]). Conclusions. – It is concluded that MTX treatment is equally effective for spontaneous EP and EP achieved by ART, two injections of MTX being more frequently required in case of ART. ß 2016 Elsevier Masson SAS. All rights reserved.
Keywords: Ectopic pregnancy Methotrexate Assisted reproductive technology In vitro fertilization
R E´ S U M E´
Mots cle´s : Grossesse extra-ute´rine Methotrexate Assistance me´dicale a` la procre´ation Fe´condation in vitro
Objectif. – Un pourcentage de 1,4 a` 1,6 des grossesses survenant a` la suite d’une assistance me´dicale a` la procre´ation (AMP) sont des grossesses extra-ute´rines (GEU). Une des options the´rapeutiques est le traitement me´dical par injection syste´mique de me´thotrexate (MTX). L’objectif de cette e´tude e´tait de comparer l’efficacite´ du traitement par MTX des GEU survenant a` la suite d’une AMP aux GEU survenant spontane´ment. Me´thodes. – Une e´tude cas-te´moins a e´te´ re´alise´e dans le service de gyne´cologie-obste´trique du CHU LaConception a` Marseille. Vingt GEU survenant a` la suite d’une AMP (groupe ART) et 60 GEU spontane´es (groupe SEP) ont rec¸u un traitement par MTX entre janvier 2002 et mai 2012. Les principaux crite`res de jugement e´taient le taux d’e´chec du traitement, le nombre d’injections de MTX administre´es et le nombre de jours avant ne´gativation des hCG. Re´sultats. – Les taux d’e´chec e´taient similaires dans le groupe ART et dans le groupe SEP : 3/20 (15 %) versus 10/60 (17 %) (OR = 0,88 [0,22–3,58]). En cas de succe`s, la dure´e avant ne´gativation des hCG ne diffe´rait pas entre les 2 groupes : 33 14 jours dans le groupe ART versus 28 13 jours dans le groupe SEP
§ See on the same subject in the same number of Gyne´cologie Obste´trique et Fertilite´, the editorial signed by Henri Marret, entitled Methotrexate allowed in ectopic pregnancy, we’re almost there! Gynecol Obstet Fertil 2016; 44. ^ Voir sur le meˆme sujet dans le meˆme nume´ro de Gyne´cologie Obste´trique & Fertilie´, l’e´ditorial signe´ de Henri Marret, intitule´ : Le me´thotrexate autorise´ dans la grossesse extra-ute´rine : on y est presque ! [Methotrexate in ectopic pregnancy is almost allowed!]. Gynecol Obstet Fertil 2016;44. http://dx.doi.org/10.1016/j.gyobfe.2016.04.008. * Corresponding author. E-mail address: [email protected] (A. Agostini).
http://dx.doi.org/10.1016/j.gyobfe.2016.04.004 1297-9589/ß 2016 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Ohannessian A, et al. Methotrexate treatment for ectopic pregnancy after assisted reproductive technology: A case-control study. Gyne´cologie Obste´trique & Fertilite´ (2016), http://dx.doi.org/10.1016/j.gyobfe.2016.04.004
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GYOBFE-2923; No. of Pages 4 A. Ohannessian et al. / Gyne´cologie Obste´trique & Fertilite´ xxx (2016) xxx–xxx
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(p = 0,39). Le recours a` une seconde injection de MTX e´tait plus fre´quent dans le groupe ART : 10/20 (50 %) versus 10/60 (17 %) (OR = 5 [1,65–15,15]). Conclusions. – Le traitement par MTX syste´mique est aussi efficace pour les GEU spontane´es que pour les GEU survenant a` la suite d’une AMP. Le recours a` deux injections de MTX est plus fre´quent en cas d’AMP. ß 2016 Elsevier Masson SAS. Tous droits re´serve´s.
1. Introduction Ectopic pregnancy (EP) occurs in about 1.4% to 1.6% of pregnancies achieved by assisted reproductive technology (ART) [1,2]. The risk for EP following ART varies according to ART procedure type [2]. It is increased among women with a previous EP history, in case of other tubal factors of infertility, endometriosis, and multiple embryo transfer [1–4]. EP treatment options include medical treatment by uses of methotrexate systemic injection (MTX). The reported success rates of methotrexate therapy range from 63% to 96.7% [5]. This treatment allows to avoid surgery. It is indicated for women presenting a less active EP, with few symptoms and a low hCG level (the cut-off for defining a less active pregnancy varies from 1500 to 5000 IU/L according to the authors) [6–9]. Due to the close follow-up inherent to ART procedures, EP diagnosis can be done at an early stage (using early hCG plasma levels and transvaginal ultrasound) prior to the onset of clinical signs [10]. MTX treatment is a possible option in most of these cases. This treatment that can avoid surgery is of great interest for these patients already highly medicalized. However, there are few publications studying specifically the effectiveness of the MTX treatment in case of EP occurring after ART. The first aim of this study is to compare MTX treatment effectiveness for ectopic pregnancy occurring spontaneously or following ART. The second aim is to compare the number of MTX injections administrated and the recovery time. 2. Methods It is a monocentric 1:3 case-control study conducted in the department of obstetrics and gynecology at a tertiary health care center in France. Women included presented with EP. In the first group, EP occurred in women treated for infertility at the hospital’s ART center (ART group). These treatments were either intrauterine insemination (IUI) or in vitro fertilization (IVF). The control group was composed of women presenting spontaneous EP (SEP group). EP diagnosis, MTX treatment and MTX monitoring were performed in the gynecological emergency unit of the department for both SEP and ART groups. The diagnostic criteria of EP and indication of MTX treatment were identical for cases and controls. Each case of the ART group was matched to three control patients based on the same hCG plasma level at day 1 (10%). These controls were selected from the register of the gynaecological emergency unit that lists in chronological order every EP treated with MTX in the department. We have retained the first three women following the case in chronological order, with the same follow-up protocol after MTX injection [11]. EP was diagnosed in women referred for pelvic pain, vaginal bleeding, or both, who met the following criteria: positive plasma hCG (stable or rising plasma hCG level in separate measurements 48 hours apart) with an empty uterus on sonography and other sonographic signs in favour of EP: an inhomogeneous adnexal mass, an empty gestational sac with a hyperechoic ring, or an extra uterine gestational sac containing a yolk sac or fetal pole with or without cardiac activity [12,13]. The indications for MTX therapy were: absence of embryonic cardiac activity detected by transvaginal ultrasonography, hCG concentration < 5000 IU/L, ectopic pregnancy < 4 cm in size
as visualized by transvaginal ultrasonography, and the ability to participate in the follow-up [14]. Contraindications for MTX treatment for EP were hepatic or renal failure, thrombopenia, anemia, or any suspicion of tubal rupture (hemodynamic instability, severe pain, or large hemoperitoneum on sonography). Women in both groups had the same follow-up protocol after injection of MTX, as described by Stovall et al. [11]. Women received intramuscular MTX at a dose of 50 mg/m2. The day of injection was considered day one of the protocol (D1). Plasma HCG levels were measured on days four (D4) and seven (D7). If they decreased by 15% between D4 and D7, weekly monitoring continued until they fall below 15 mIU/mL. If they failed to decline by 15% between D4 and D7 or between weekly hCG titers, the MTX injection was repeated. After the second injection, hCG titers were followed with a new day one reading. If they failed to fall appropriately after a total of three injections, treatment was considered to have failed, and surgical therapy was recommended. During this study period, women with suspicion of tubal rupture or refusal of second or third MTX injections were treated surgically. MTX treatment failure was defined by the need for surgical treatment for suspicion of tubal rupture or the absence of an appropriate hCG decline after three injections or the woman’s refusal of a second or third MTX injection. The women’s characteristics studied were: age, body mass index, gestity, parity, current smoking, history of previous EP, plasma HCG level at D1. Recovery time was defined by the time until the hCG level drops below 2 IU/L after D1. Data analysis was carried out with the Statistics Package for Social Sciences (SPSS 17.0). Qualitative data were compared by calculating the odds ratio (OR) with their 95% confidence intervals. Quantitative data were analyzed using paired sample t-test or Wilcoxon test, as appropriate. A P-value < 0.05 was considered statistically significant. This study was approved by the Committee of Ethics for Research in Obstetrics and Gynecology (CEROG 2012-GYN-08-02). Informed consent was obtained from all participants. 3. Results Between January 2002 and May 2012, 35 women were diagnosed with EP following treatment received at the ART center. Fifteen of those women were treated surgically in first intention. Among these 20 EP treated by MTX (57%), 17 occurred after IVF and 3 after IUI. These 20 EP (ART group) were matched to 60 spontaneous EP (group SEP) also treated with MTX in first intention. During the study period, 60% of spontaneous EP were treated with MTX in first intention. None of the characteristics were significantly different between the two groups (Table 1). There was no difference in the smoking status of women (29% in the ART group versus 49%: OR = 0.41 [0.07–2.29]). Prior history of EP were not statistically more frequent in the ART group compared to the SEP group (6% versus 23%: OR = 0.21 [0.03–1.74]). The treatment failure rate was not significantly different between the ART group and the SEP group (3/20 [15%] versus
Please cite this article in press as: Ohannessian A, et al. Methotrexate treatment for ectopic pregnancy after assisted reproductive technology: A case-control study. Gyne´cologie Obste´trique & Fertilite´ (2016), http://dx.doi.org/10.1016/j.gyobfe.2016.04.004
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GYOBFE-2923; No. of Pages 4 A. Ohannessian et al. / Gyne´cologie Obste´trique & Fertilite´ xxx (2016) xxx–xxx Table 1 Women characteristics. ART group, n = 20
SEP group, n = 60
Value of P
ˆ ge (years) (M SD) A 33.5 6.0 31.5 6.0 0.57a Body mass index (kg/m2) 24.0 3.0 24.0 6.0 0.27a (M SD) Gestity (n) (M SD) 1.6 0.7 3 3.0 0.01a Parity (n) (M SD) 0.2 0.4 1.1 1.4 0.01a Day 1 hCG level (UI/L) 1724.0 1865.0 1690.0 1778.0 0.09b (M SD) M SD: mean standard deviation; ART group: ectopic pregnancies achieved by assisted reproduction technology; SEP group: spontaneous ectopic pregnancies. a Paired sample t-test. b Wilcoxon test.
10/60 [17%] respectively, OR = 0.88 [0.22 to 3.58]). All women who underwent surgery were operated in emergency for suspicion of tubal rupture after a single injection of MTX, excepted one patient in the group ART who refused a second injection of MTX. The use of two MTX injections was significantly more frequent in the ART group (10/20 [50%] versus 10/60 [17%], OR = 5 [1.65– 15.15]). No woman received a third MTX injection. In case of success, the recovery time was not significantly different between the ART group and the SEP group (33 14 days versus 28 13 days [P = 0.39]).
4. Discussion In the present study, effectiveness of MTX treatment seems to be similar for spontaneous EP and ART EP. In case of success, the recovery time was equal in both groups. However, two MTX injections were required more frequently in case of EP after ART. Cases in both groups were matched based on hCG plasma level at day 1. The hCG plasma level at day 1 is the main risk factor for MTX treatment failure of EP [15–18]. By this way, comparability of the two groups was ensured. The number of controls, three for one case, was arbitrarily chosen to increase the power of the study, without being too distant in time relative cases of the ART group. The study period was long but the treatment protocol was the same throughout the study period in both groups. The limitations of this single-center study relate to the retrospective nature of the data analysis. Moreover, the relatively small sample size could explain the absence of significant difference between the two groups regarding the failure rate, due to a lack of power. Besides, 3 women with IUI treatment were included in the ART group. It was shown that the rate of EP is higher after IVF in comparison with IUI (1.4 vs. 1.1%, P = 0.043) [2]. It is therefore possible that the pathophysiological mechanisms of EP is different depending on the type of ART treatment. Nevertheless, it is only a matter of 3 women in a group of 20 women. We might think that any impact would not change significantly the results. Several studies have reported series of ART EP treated with MTX to evaluate his impact on ovarian reserve [19–27]. In these studies, the women included were women with a successful MTX treatment. Thus, the success rate of MTX is often not described. Boots et al. reported 66 women with an EP after IVF [19]. The failure rate was 4/66 (6%) with 19/66 requiring 2 injections (29%). McLaren et al. reported a failure rate of 5/39 women (13%), with an average of 1.27 MTX injections [20]. Hill et al. reported 153 women treated by MTX: 58 (38%) requiring one injection, 74 (48%) requiring 2 injections, and 21 (14%) requiring 3 injections [27]. To our knowledge, there is no comparative case-control study that compared the success rate in case of spontaneous EP versus EP following ART.
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The more frequent need for a second MTX injection in case of EP following ART cannot be explained by a follow-up bias because the follow-up protocol was identical in both groups during the study period. The reduced effectiveness of the first injection in case of EP following ART may be due to a different physiological context, such as hormone levels (hCG, œstradiol, progesterone) or implantation mechanisms. In the literature, the failure risk factors of treatment have been more studied than the factors predicting the need for another injection. In case of spontaneous EP, it has been reported more failures in case of previous EP history, higher folic acid or progesterone serum levels [15,28,29]. Precisely, women who need ART often have a history of EP, take folic acid supplements for a long time and progesterone for luteal phase support. However, more recently a study showed that the progesterone serum level was not correlated with the failure rate or the need for a second MTX injection [30]. In conclusion, MTX seems to be a reasonable and effective treatment for EP following ART. However, it seems that the use of multiple injections is more common. These elements need to be confirmed in larger studies. 5. Conclusion It is concluded that MTX treatment is equally effective for spontaneous EP and ART EP, two injections of methotrexate being more frequently required in case of ART. Disclosure of interest The authors declare that they have no competing interest. References [1] Perkins KM, Boulet SL, Kissin DM, Jamieson DJ, National ART Surveillance (NASS) Group. Risk of ectopic pregnancy associated with assisted reproductive technology in the United States, 2001–2011. Obstet Gynecol 2015;125(1): 70–8. [2] Santos-Ribeiro S, Tournaye H, Polyzos NP. Trends in ectopic pregnancy rates following assisted reproductive technologies in the UK: a 12-year nationwide analysis including 160,000 pregnancies. Hum Reprod 2016;31(2):393–402. [3] Bu Z, Xiong Y, Wang K, Sun Y. Risk factors for ectopic pregnancy in assisted reproductive technology: a 6-year, single-center study. Fertil Steril 2016. http:// dx.doi.org/10.1016/j.fertnstert.2016.02.035 [pii: S0015-0282(16)30008-5]. [4] Li Z, Sullivan EA, Chapman M, Farquhar C, Wang YA. Risk of ectopic pregnancy lowest with transfer of single frozen blastocyst. Hum Reprod 2015;30(9): 2048–54. [5] Barnhart KT, Gosman G, Ashby R, Sammel M. The medical management of ectopic pregnancy: a meta-analysis comparing ‘‘single dose’’ and ‘‘multidose’’ regimens. Obstet Gynecol 2003;101:778–84. [6] Lipscomb GH. Medical therapy for ectopic pregnancy. Semin Reprod Med 2007;25:93–8. [7] Lipscomb GH. Medical management of ectopic pregnancy. Clin Obstet Gynecol 2012;55:424–32. [8] American College of Obstetricians and Gynecologists. ACOG practice bulletin. Medical management of tubal pregnancy. Number 3, December 1998. Clinical management guidelines for obstetrician-gynecologists. Int J Gynaecol Obstet 1999;65:97–103. [9] Goffinet F, Dreyfus M, Madelenat P. Colle`ge national des gyne´cologues et obste´triciens franc¸ais Recommendations for clinical practice: management of extra-uterine pregnancy Gynecol Obstet Fertil 2004;32(2):180–5 [discussion 180]. [10] Van Mello NM, Mol F, Ankum WM, Mol BW, Van der Veen F, et al. Ectopic pregnancy: how the diagnostic and therapeutic management has changed. Fertil Steril 2012;98:1066–73. [11] Stovall TG, Ling FW, Gray LA. Single-dose methotrexate for treatment of ectopic pregnancy. Obstet Gynecol 1991;77:754–7. [12] Condous G, Okaro E, Khalid A, Lu C, Van Huffel S, et al. The accuracy of transvaginal ultrasonography for the diagnosis of ectopic pregnancy prior to surgery. Hum Reprod 2005;20:1404–9. [13] Levine D. Ectopic pregnancy. Radiology 2007;245:385–97. [14] Practice Committee of American Society for Reproductive Medicine. Medical treatment of ectopic pregnancy. Fertil Steril 2008;90(5 Suppl.):S206–12. [15] Lipscomb GH, McCord ML, Stovall TG, Huff G, Portera SG, et al. Predictors of success of methotrexate treatment in women with tubal ectopic pregnancies. N Engl J Med 1999;341:1974–8.
Please cite this article in press as: Ohannessian A, et al. Methotrexate treatment for ectopic pregnancy after assisted reproductive technology: A case-control study. Gyne´cologie Obste´trique & Fertilite´ (2016), http://dx.doi.org/10.1016/j.gyobfe.2016.04.004
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[16] Menon S, Colins J, Barnhart KT. Establishing a human chorionic gonadotropin cutoff to guide methotrexate treatment of ectopic pregnancy: a systematic review. Fertil Steril 2007;87:481–4. [17] Nazac A, Gervaise A, Bouyer J, De Tayrac R, Capella-Allouc S, et al. Predictors of success in methotrexate treatment of women with unruptured tubal pregnancies. Ultrasound Obstet Gynecol 2003;21:181–5. [18] Moon MH, Lee YH, Lim KT, Yang JH, Park SH. Outcome prediction for treatment of tubal pregnancy using an intramuscular methotrexate protocol. J Ultrasound Med 2008;27:1461–7. [19] Boots CE, Gustofson RL, Feinberg EC. Does methotrexate administration for ectopic pregnancy after in vitro fertilization impact ovarian reserve or ovarian responsiveness? Fertil Steril 2013;100:1590–3. [20] McLaren JF, Burney RO, Milki AA, Westphal LM, Dahan MH, et al. Effect of methotrexate exposure on subsequent fertility in women undergoing controlled ovarian stimulation. Fertil Steril 2009;92:515–9. [21] Orvieto R, Kruchkovich J, Zohav E, Rabinson J, Anteby EY, et al. Does methotrexate treatment for ectopic pregnancy influence the patient’s performance during a subsequent in vitro fertilization/embryo transfer cycle? Fertil Steril 2007;88:1685–6. [22] Provansal M, Agostini A, Lacroix O, Gerbeau S, Grillo JM, et al. Ultrasound monitoring in patients undergoing in-vitro fertilization after methotrexate treatment for ectopic pregnancy. Ultrasound Obstet Gynecol 2009;34:715–9. [23] Oriol B, Barrio A, Pacheco A, Serna J, Zuzuarregui JL, et al. Systemic methotrexate to treat ectopic pregnancy does not affect ovarian reserve. Fertil Steril 2008;90:1579–82.
[24] Wiser A, Gilbert A, Nahum R, Orvieto R, Haas J, Hourvitz A, et al. Effects of treatment of ectopic pregnancy with methotrexate or salpingectomy in the subsequent IVF cycle. Reprod Biomed Online 2013;26:449–55. [25] Ohannessian A, Loundou A, Courbie`re B, Cravello L, Agostini A. Ovarian responsiveness in women receiving fertility treatment after methotrexate for ectopic pregnancy: a systematic review and meta-analysis. Hum Reprod 2014;29:1949–56. [26] Boots CE, Hill MJ, Feinberg EC, Lathi RB, Fowler SA, Jungheim ES. Methotrexate does not affect ovarian reserve or subsequent assisted reproductive technology outcomes. J Assist Reprod Genet 2016. http://dx.doi.org/10.1007/s10815016-0683-7 [Epub ahead of print]. [27] Hill MJ, Cooper JC, Levy G, Alford C, Richter KS, DeCherney AH, et al. Ovarian reserve and subsequent assisted reproduction outcomes after methotrexate therapy for ectopic pregnancy or pregnancy of unknown location. Fertil Steril 2014;101:413–9. [28] Lipscomb GH, Givens VA, Meyer NL, Bran D. Previous ectopic pregnancy as a predictor of failure of systemic methotrexate therapy. Fertil Steril 2004; 81(5):1221–4. [29] Takacs P, Rodriguez L, Laibl V, Pietro P, Kang J. Relationship of high pretreatment folic acid level and failure of methotrexate in ectopic pregnancy: a pilot study. J Reprod Med 2004;49(9):713–6. [30] Wu J, Ludlow JP, De Vries B, Black K, Beale P. Single-dose methotrexate treatment for ectopic pregnancy and pregnancy of unknown location and progesterone as a predictor of success. Aust N Z J Obstet Gynaecol 2014; 54(5):469–74.
Please cite this article in press as: Ohannessian A, et al. Methotrexate treatment for ectopic pregnancy after assisted reproductive technology: A case-control study. Gyne´cologie Obste´trique & Fertilite´ (2016), http://dx.doi.org/10.1016/j.gyobfe.2016.04.004
GYOBFE-2923; No. of Pages 4 Gyne´cologie Obste´trique & Fertilite´ xxx (2016) xxx–xxx
Available online at
ScienceDirect www.sciencedirect.com
Original article
Methotrexate treatment for ectopic pregnancy after assisted reproductive technology: A case-control study§ Traitement par me´thotrexate des grossesses extra-ute´rines issues d’une assistance me´dicale a` la procre´ation^ A. Ohannessian, P. Crochet, B. Courbiere, A. Gnisci, A. Agostini * Service de gyne´cologie-obste´trique, hoˆpital de La Conception, 147, boulevard Baille, 13005 Marseille, France
A R T I C L E I N F O
A B S T R A C T
Article history: Received 17 February 2016 Accepted 11 April 2016 Available online xxx
Objectives. – Ectopic pregnancy (EP) occurs in 2% to 5.6% of pregnancies achieved by assisted reproductive technology (ART). EP treatment options include medical treatment by uses of methotrexate (MTX) systemic injection. The objective of this study was to compare MTX treatment effectiveness for EP occurring spontaneously or following ART. Methods. – A case-control study performed in the department of obstetrics and gynecology at a tertiary health care center in France. Twenty EP achieved by ART (ART group) and 60 spontaneous EP (SEP group) received MTX treatment between January 2002 and May 2012. The main outcome measures were MTX treatment failure rates, number of MTX injections administered and recovery time. Results. – MTX treatment failure rates observed in ART and SEP groups were similar (3/20 [15%] versus 10/60 [17%]: OR = 0.88 [0.22–3.58]). Mean duration of recovery time in patients with successful MTX treatment did not differ between ART and SEP groups (33 14 days versus 28 13 days, P = 0.39). A second MTX injection was required more frequently in ART group than in SEP group (10/20 [50%] versus 10/60 [17%]: OR = 5 [1.65–15.15]). Conclusions. – It is concluded that MTX treatment is equally effective for spontaneous EP and EP achieved by ART, two injections of MTX being more frequently required in case of ART. ß 2016 Elsevier Masson SAS. All rights reserved.
Keywords: Ectopic pregnancy Methotrexate Assisted reproductive technology In vitro fertilization
R E´ S U M E´
Mots cle´s : Grossesse extra-ute´rine Methotrexate Assistance me´dicale a` la procre´ation Fe´condation in vitro
Objectif. – Un pourcentage de 1,4 a` 1,6 des grossesses survenant a` la suite d’une assistance me´dicale a` la procre´ation (AMP) sont des grossesses extra-ute´rines (GEU). Une des options the´rapeutiques est le traitement me´dical par injection syste´mique de me´thotrexate (MTX). L’objectif de cette e´tude e´tait de comparer l’efficacite´ du traitement par MTX des GEU survenant a` la suite d’une AMP aux GEU survenant spontane´ment. Me´thodes. – Une e´tude cas-te´moins a e´te´ re´alise´e dans le service de gyne´cologie-obste´trique du CHU LaConception a` Marseille. Vingt GEU survenant a` la suite d’une AMP (groupe ART) et 60 GEU spontane´es (groupe SEP) ont rec¸u un traitement par MTX entre janvier 2002 et mai 2012. Les principaux crite`res de jugement e´taient le taux d’e´chec du traitement, le nombre d’injections de MTX administre´es et le nombre de jours avant ne´gativation des hCG. Re´sultats. – Les taux d’e´chec e´taient similaires dans le groupe ART et dans le groupe SEP : 3/20 (15 %) versus 10/60 (17 %) (OR = 0,88 [0,22–3,58]). En cas de succe`s, la dure´e avant ne´gativation des hCG ne diffe´rait pas entre les 2 groupes : 33 14 jours dans le groupe ART versus 28 13 jours dans le groupe SEP
§ See on the same subject in the same number of Gyne´cologie Obste´trique et Fertilite´, the editorial signed by Henri Marret, entitled Methotrexate allowed in ectopic pregnancy, we’re almost there! Gynecol Obstet Fertil 2016; 44. ^ Voir sur le meˆme sujet dans le meˆme nume´ro de Gyne´cologie Obste´trique & Fertilie´, l’e´ditorial signe´ de Henri Marret, intitule´ : Le me´thotrexate autorise´ dans la grossesse extra-ute´rine : on y est presque ! [Methotrexate in ectopic pregnancy is almost allowed!]. Gynecol Obstet Fertil 2016;44. http://dx.doi.org/10.1016/j.gyobfe.2016.04.008. * Corresponding author. E-mail address: [email protected] (A. Agostini).
http://dx.doi.org/10.1016/j.gyobfe.2016.04.004 1297-9589/ß 2016 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Ohannessian A, et al. Methotrexate treatment for ectopic pregnancy after assisted reproductive technology: A case-control study. Gyne´cologie Obste´trique & Fertilite´ (2016), http://dx.doi.org/10.1016/j.gyobfe.2016.04.004
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GYOBFE-2923; No. of Pages 4 A. Ohannessian et al. / Gyne´cologie Obste´trique & Fertilite´ xxx (2016) xxx–xxx
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(p = 0,39). Le recours a` une seconde injection de MTX e´tait plus fre´quent dans le groupe ART : 10/20 (50 %) versus 10/60 (17 %) (OR = 5 [1,65–15,15]). Conclusions. – Le traitement par MTX syste´mique est aussi efficace pour les GEU spontane´es que pour les GEU survenant a` la suite d’une AMP. Le recours a` deux injections de MTX est plus fre´quent en cas d’AMP. ß 2016 Elsevier Masson SAS. Tous droits re´serve´s.
1. Introduction Ectopic pregnancy (EP) occurs in about 1.4% to 1.6% of pregnancies achieved by assisted reproductive technology (ART) [1,2]. The risk for EP following ART varies according to ART procedure type [2]. It is increased among women with a previous EP history, in case of other tubal factors of infertility, endometriosis, and multiple embryo transfer [1–4]. EP treatment options include medical treatment by uses of methotrexate systemic injection (MTX). The reported success rates of methotrexate therapy range from 63% to 96.7% [5]. This treatment allows to avoid surgery. It is indicated for women presenting a less active EP, with few symptoms and a low hCG level (the cut-off for defining a less active pregnancy varies from 1500 to 5000 IU/L according to the authors) [6–9]. Due to the close follow-up inherent to ART procedures, EP diagnosis can be done at an early stage (using early hCG plasma levels and transvaginal ultrasound) prior to the onset of clinical signs [10]. MTX treatment is a possible option in most of these cases. This treatment that can avoid surgery is of great interest for these patients already highly medicalized. However, there are few publications studying specifically the effectiveness of the MTX treatment in case of EP occurring after ART. The first aim of this study is to compare MTX treatment effectiveness for ectopic pregnancy occurring spontaneously or following ART. The second aim is to compare the number of MTX injections administrated and the recovery time. 2. Methods It is a monocentric 1:3 case-control study conducted in the department of obstetrics and gynecology at a tertiary health care center in France. Women included presented with EP. In the first group, EP occurred in women treated for infertility at the hospital’s ART center (ART group). These treatments were either intrauterine insemination (IUI) or in vitro fertilization (IVF). The control group was composed of women presenting spontaneous EP (SEP group). EP diagnosis, MTX treatment and MTX monitoring were performed in the gynecological emergency unit of the department for both SEP and ART groups. The diagnostic criteria of EP and indication of MTX treatment were identical for cases and controls. Each case of the ART group was matched to three control patients based on the same hCG plasma level at day 1 (10%). These controls were selected from the register of the gynaecological emergency unit that lists in chronological order every EP treated with MTX in the department. We have retained the first three women following the case in chronological order, with the same follow-up protocol after MTX injection [11]. EP was diagnosed in women referred for pelvic pain, vaginal bleeding, or both, who met the following criteria: positive plasma hCG (stable or rising plasma hCG level in separate measurements 48 hours apart) with an empty uterus on sonography and other sonographic signs in favour of EP: an inhomogeneous adnexal mass, an empty gestational sac with a hyperechoic ring, or an extra uterine gestational sac containing a yolk sac or fetal pole with or without cardiac activity [12,13]. The indications for MTX therapy were: absence of embryonic cardiac activity detected by transvaginal ultrasonography, hCG concentration < 5000 IU/L, ectopic pregnancy < 4 cm in size
as visualized by transvaginal ultrasonography, and the ability to participate in the follow-up [14]. Contraindications for MTX treatment for EP were hepatic or renal failure, thrombopenia, anemia, or any suspicion of tubal rupture (hemodynamic instability, severe pain, or large hemoperitoneum on sonography). Women in both groups had the same follow-up protocol after injection of MTX, as described by Stovall et al. [11]. Women received intramuscular MTX at a dose of 50 mg/m2. The day of injection was considered day one of the protocol (D1). Plasma HCG levels were measured on days four (D4) and seven (D7). If they decreased by 15% between D4 and D7, weekly monitoring continued until they fall below 15 mIU/mL. If they failed to decline by 15% between D4 and D7 or between weekly hCG titers, the MTX injection was repeated. After the second injection, hCG titers were followed with a new day one reading. If they failed to fall appropriately after a total of three injections, treatment was considered to have failed, and surgical therapy was recommended. During this study period, women with suspicion of tubal rupture or refusal of second or third MTX injections were treated surgically. MTX treatment failure was defined by the need for surgical treatment for suspicion of tubal rupture or the absence of an appropriate hCG decline after three injections or the woman’s refusal of a second or third MTX injection. The women’s characteristics studied were: age, body mass index, gestity, parity, current smoking, history of previous EP, plasma HCG level at D1. Recovery time was defined by the time until the hCG level drops below 2 IU/L after D1. Data analysis was carried out with the Statistics Package for Social Sciences (SPSS 17.0). Qualitative data were compared by calculating the odds ratio (OR) with their 95% confidence intervals. Quantitative data were analyzed using paired sample t-test or Wilcoxon test, as appropriate. A P-value < 0.05 was considered statistically significant. This study was approved by the Committee of Ethics for Research in Obstetrics and Gynecology (CEROG 2012-GYN-08-02). Informed consent was obtained from all participants. 3. Results Between January 2002 and May 2012, 35 women were diagnosed with EP following treatment received at the ART center. Fifteen of those women were treated surgically in first intention. Among these 20 EP treated by MTX (57%), 17 occurred after IVF and 3 after IUI. These 20 EP (ART group) were matched to 60 spontaneous EP (group SEP) also treated with MTX in first intention. During the study period, 60% of spontaneous EP were treated with MTX in first intention. None of the characteristics were significantly different between the two groups (Table 1). There was no difference in the smoking status of women (29% in the ART group versus 49%: OR = 0.41 [0.07–2.29]). Prior history of EP were not statistically more frequent in the ART group compared to the SEP group (6% versus 23%: OR = 0.21 [0.03–1.74]). The treatment failure rate was not significantly different between the ART group and the SEP group (3/20 [15%] versus
Please cite this article in press as: Ohannessian A, et al. Methotrexate treatment for ectopic pregnancy after assisted reproductive technology: A case-control study. Gyne´cologie Obste´trique & Fertilite´ (2016), http://dx.doi.org/10.1016/j.gyobfe.2016.04.004
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GYOBFE-2923; No. of Pages 4 A. Ohannessian et al. / Gyne´cologie Obste´trique & Fertilite´ xxx (2016) xxx–xxx Table 1 Women characteristics. ART group, n = 20
SEP group, n = 60
Value of P
ˆ ge (years) (M SD) A 33.5 6.0 31.5 6.0 0.57a Body mass index (kg/m2) 24.0 3.0 24.0 6.0 0.27a (M SD) Gestity (n) (M SD) 1.6 0.7 3 3.0 0.01a Parity (n) (M SD) 0.2 0.4 1.1 1.4 0.01a Day 1 hCG level (UI/L) 1724.0 1865.0 1690.0 1778.0 0.09b (M SD) M SD: mean standard deviation; ART group: ectopic pregnancies achieved by assisted reproduction technology; SEP group: spontaneous ectopic pregnancies. a Paired sample t-test. b Wilcoxon test.
10/60 [17%] respectively, OR = 0.88 [0.22 to 3.58]). All women who underwent surgery were operated in emergency for suspicion of tubal rupture after a single injection of MTX, excepted one patient in the group ART who refused a second injection of MTX. The use of two MTX injections was significantly more frequent in the ART group (10/20 [50%] versus 10/60 [17%], OR = 5 [1.65– 15.15]). No woman received a third MTX injection. In case of success, the recovery time was not significantly different between the ART group and the SEP group (33 14 days versus 28 13 days [P = 0.39]).
4. Discussion In the present study, effectiveness of MTX treatment seems to be similar for spontaneous EP and ART EP. In case of success, the recovery time was equal in both groups. However, two MTX injections were required more frequently in case of EP after ART. Cases in both groups were matched based on hCG plasma level at day 1. The hCG plasma level at day 1 is the main risk factor for MTX treatment failure of EP [15–18]. By this way, comparability of the two groups was ensured. The number of controls, three for one case, was arbitrarily chosen to increase the power of the study, without being too distant in time relative cases of the ART group. The study period was long but the treatment protocol was the same throughout the study period in both groups. The limitations of this single-center study relate to the retrospective nature of the data analysis. Moreover, the relatively small sample size could explain the absence of significant difference between the two groups regarding the failure rate, due to a lack of power. Besides, 3 women with IUI treatment were included in the ART group. It was shown that the rate of EP is higher after IVF in comparison with IUI (1.4 vs. 1.1%, P = 0.043) [2]. It is therefore possible that the pathophysiological mechanisms of EP is different depending on the type of ART treatment. Nevertheless, it is only a matter of 3 women in a group of 20 women. We might think that any impact would not change significantly the results. Several studies have reported series of ART EP treated with MTX to evaluate his impact on ovarian reserve [19–27]. In these studies, the women included were women with a successful MTX treatment. Thus, the success rate of MTX is often not described. Boots et al. reported 66 women with an EP after IVF [19]. The failure rate was 4/66 (6%) with 19/66 requiring 2 injections (29%). McLaren et al. reported a failure rate of 5/39 women (13%), with an average of 1.27 MTX injections [20]. Hill et al. reported 153 women treated by MTX: 58 (38%) requiring one injection, 74 (48%) requiring 2 injections, and 21 (14%) requiring 3 injections [27]. To our knowledge, there is no comparative case-control study that compared the success rate in case of spontaneous EP versus EP following ART.
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The more frequent need for a second MTX injection in case of EP following ART cannot be explained by a follow-up bias because the follow-up protocol was identical in both groups during the study period. The reduced effectiveness of the first injection in case of EP following ART may be due to a different physiological context, such as hormone levels (hCG, œstradiol, progesterone) or implantation mechanisms. In the literature, the failure risk factors of treatment have been more studied than the factors predicting the need for another injection. In case of spontaneous EP, it has been reported more failures in case of previous EP history, higher folic acid or progesterone serum levels [15,28,29]. Precisely, women who need ART often have a history of EP, take folic acid supplements for a long time and progesterone for luteal phase support. However, more recently a study showed that the progesterone serum level was not correlated with the failure rate or the need for a second MTX injection [30]. In conclusion, MTX seems to be a reasonable and effective treatment for EP following ART. However, it seems that the use of multiple injections is more common. These elements need to be confirmed in larger studies. 5. Conclusion It is concluded that MTX treatment is equally effective for spontaneous EP and ART EP, two injections of methotrexate being more frequently required in case of ART. Disclosure of interest The authors declare that they have no competing interest. References [1] Perkins KM, Boulet SL, Kissin DM, Jamieson DJ, National ART Surveillance (NASS) Group. Risk of ectopic pregnancy associated with assisted reproductive technology in the United States, 2001–2011. Obstet Gynecol 2015;125(1): 70–8. [2] Santos-Ribeiro S, Tournaye H, Polyzos NP. Trends in ectopic pregnancy rates following assisted reproductive technologies in the UK: a 12-year nationwide analysis including 160,000 pregnancies. Hum Reprod 2016;31(2):393–402. [3] Bu Z, Xiong Y, Wang K, Sun Y. Risk factors for ectopic pregnancy in assisted reproductive technology: a 6-year, single-center study. Fertil Steril 2016. http:// dx.doi.org/10.1016/j.fertnstert.2016.02.035 [pii: S0015-0282(16)30008-5]. [4] Li Z, Sullivan EA, Chapman M, Farquhar C, Wang YA. Risk of ectopic pregnancy lowest with transfer of single frozen blastocyst. Hum Reprod 2015;30(9): 2048–54. [5] Barnhart KT, Gosman G, Ashby R, Sammel M. The medical management of ectopic pregnancy: a meta-analysis comparing ‘‘single dose’’ and ‘‘multidose’’ regimens. Obstet Gynecol 2003;101:778–84. [6] Lipscomb GH. Medical therapy for ectopic pregnancy. Semin Reprod Med 2007;25:93–8. [7] Lipscomb GH. Medical management of ectopic pregnancy. Clin Obstet Gynecol 2012;55:424–32. [8] American College of Obstetricians and Gynecologists. ACOG practice bulletin. Medical management of tubal pregnancy. Number 3, December 1998. Clinical management guidelines for obstetrician-gynecologists. Int J Gynaecol Obstet 1999;65:97–103. [9] Goffinet F, Dreyfus M, Madelenat P. Colle`ge national des gyne´cologues et obste´triciens franc¸ais Recommendations for clinical practice: management of extra-uterine pregnancy Gynecol Obstet Fertil 2004;32(2):180–5 [discussion 180]. [10] Van Mello NM, Mol F, Ankum WM, Mol BW, Van der Veen F, et al. Ectopic pregnancy: how the diagnostic and therapeutic management has changed. Fertil Steril 2012;98:1066–73. [11] Stovall TG, Ling FW, Gray LA. Single-dose methotrexate for treatment of ectopic pregnancy. Obstet Gynecol 1991;77:754–7. [12] Condous G, Okaro E, Khalid A, Lu C, Van Huffel S, et al. The accuracy of transvaginal ultrasonography for the diagnosis of ectopic pregnancy prior to surgery. Hum Reprod 2005;20:1404–9. [13] Levine D. Ectopic pregnancy. Radiology 2007;245:385–97. [14] Practice Committee of American Society for Reproductive Medicine. Medical treatment of ectopic pregnancy. Fertil Steril 2008;90(5 Suppl.):S206–12. [15] Lipscomb GH, McCord ML, Stovall TG, Huff G, Portera SG, et al. Predictors of success of methotrexate treatment in women with tubal ectopic pregnancies. N Engl J Med 1999;341:1974–8.
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Please cite this article in press as: Ohannessian A, et al. Methotrexate treatment for ectopic pregnancy after assisted reproductive technology: A case-control study. Gyne´cologie Obste´trique & Fertilite´ (2016), http://dx.doi.org/10.1016/j.gyobfe.2016.04.004