Perrine Capmas, Jean Bouyer and Hervé Fernandez
© Springer International Publishing Switzerland 2015 T. Tulandi (ed.), Ectopic Pregnancy,
DOI 10.1007/978-3-319-11140-7_21 P. Capmas () · H. Fernandez
Service de Gynécologie Obstétrique, Hôpital Bicêtre, GHU Sud, AP-HP, 78, avenue du Général Leclerc, 94276 Le Kremlin Bicêtre Cedex, France e-mail: [email protected]
Univ Paris Sud, 94276 Le Kremlin Bicêtre, France J. Bouyer · P. Capmas · H. Fernandez
Centre of research in Epidemiology and population health (CESP), Inserm, U1018, 94276 Le Kremlin Bicêtre, France
e-mail: [email protected] H. Fernandez
BICETRE, 78 rue du General Leclerk, 94270 Le Kremlin Bicetre, France e-mail: [email protected]
Case Study
The patient was a 35-year-old woman who presented at 6 weeks’
gestation with abdominal pain and vaginal bleeding. Her past story revealed severe preeclampsia and cesarean delivery at 34 weeks’
gestation. Ultrasound examination showed a left tubal ectopic preg- nancy (15 mm hematosalpinx) without hemoperitoneum. The se- rum human chorionic gonadotropin (hCG) level was 1500 IU/l. She was then treated with a single dose of methotrexate intramuscularly
P. Capmas et al.
154
(1 mg/kg body weight). The hCG levels were 1980 IU/L on day 4 of injection, 1458 IU/L on day 7, 2 IU/L on day 28.
My Management
a. Agree with the above management.
b. I prefer an expectant management.
c. For fertility reason, surgical management is a better treatment.
Diagnosis and Assessment
Ectopic tubal pregnancy is still a leading cause of maternal mortal- ity in the first trimester of pregnancy. Early diagnosis and treat- ment has allowed medical management and minimally invasive treatment with fertility preservation.
There are two groups of patients with ectopic tubal pregnancy.
The first group consists of women who can be managed by medical treatment or conservative surgery (salpingostomy), and the second group needs to be treated surgically (conservative or radical). Ec- topic tubal pregnancy is also often associated with a difficulty to conceive. There are data on spontaneous subsequent fertility after ectopic pregnancy but very few about fertility after assisted repro- duction treatment (ART). There are also few published data on the indications of ART after a previous ectopic pregnancy [1].
Management
This group of patients can be treated medically or with conserva- tive surgery by salpingostomy. Many criteria have been used to define this group. These include the initial serum hCG level, pro- gesterone level, tubal diameter, and hemoperitoneum [2–8]. Some composite scores have also been used [9, 10]. The most commonly
used criterion is the initial hCG level [11], but there has been no agreement on the cutoff level [3, 5, 6, 8].
Published data on fertility after ectopic pregnancy are mainly observational. However, prospective studies from ectopic pregnan- cy registries in two regions of France (Auvergne and Nord) have concluded that fertility is similar after medical treatment and con- servative surgery, but lower after radical surgery [12–15].
In the Auvergne registry, 1064 women were included between 1992 and 2008. The rate of subsequent fertility 2 years after con- servative surgery as well as after medical treatment was similar (76 %). However, the number of women with a medical treatment (119 women) was low and those with a conservative surgery (646 women) included in the registry consisted of patients who could be treated with medical, conservative, or radical surgery [12].
Three randomized trials comparing medical treatment (intra- muscular or local injections of methotrexate) and conservative surgery found different results about subsequent fertility, but they probably lacked the power to reach a definitive conclusion [16–
18]. The studies were designed to compare efficacy of treatment with low statistical power.
Dias Pereira et al. evaluated fertility after treatment of ectopic pregnancy in 74 women. Spontaneous intrauterine pregnancy oc- curred in 36 % of cases after medical treatment and in 43 % after con- servative surgery ( p: nonsignificant, relative risk (RR): 0.89 (0.42–
1.9)) [16]. In another study of 34 women, Zilber et al. found that subsequent intrauterine pregnancy rates after conservative surgery (83.5 %) and after local methotrexate treatment (81 %) were compa- rable [17]. On the other hand, Fernandez et al. reported that the rate of intrauterine pregnancy was 96.3 % after local methotrexate treat- ment ( n: 27) and 62 % after conservative surgery (n: 29; p < 0.05) [18]. The numbers of cases in those studies are relatively low.
A larger and multicenter randomized trial (Demeter study) in- volved 179 women with ectopic pregnancy treated with methotrex- ate or conservative surgery [19]. The subsequent spontaneous intra- uterine pregnancy rate after medical treatment was 67 % and after conservative surgical treatment was 71 % ( p: nonsignificant) [19].
The results of the main studies are demonstrated in Table 21.1.
P. Capmas et al.
156
Table 21.1 Spontaneous intrauterine pregnancy rate after medical or conservative surgical management (salpingostomy) StudyType of studyMedical treatmentConservative surgeryHRp n Spontaneous IUP
a rate (%)n
Spontaneous IUP
a rate (%) De Bennetot et al. [12]Prospective observa- tional (registry)11976 (0.65–0.85)64676 (0.73–0.80)1.07 (0.84–1.36) Dias Pereira et al. [16]Randomized trial343640430.89 (0.42–1.9) Zilber et al. [17]Randomized trial16811883.50.99 Fernandez et al. [18]Randomized trial2796.32962 < 0.05 Fernandez et al. [19]Randomized trial877182670.85 (0.59–1.22)0.37 aIUP intrauterine pregnancy, HR hazards ratio
In the Demeter trial, the rates of recurrent tubal pregnancy were 12 % after medical management and 9 % after conservative surgery ( p: nonsignificant) [19]. Similar findings were found in the Au- vergne registry [12]. The study demonstrates that subsequent fertil- ity after medical therapy or conservative surgery in this group of patients is comparable.
Symptomatic Tubal Pregnancy
In this group of patients, a surgical management is required and it could be either conservative (salpingostomy) or radical surgery (salpingectomy). The best data comparing fertility rate after sal- pingostomy or salpingectomy come from the registry and the two randomized trials computed for fertility analyses.
The Auvergne registry reported a higher crude cumulative intra- uterine pregnancy rate after salpingostomy (76 %) than after salpin- gectomy (67 %; p < 0.05) [12]. However, in a multivariate analysis, no significant difference between the treatments was found. In the subgroups of women with a history of infertility, tubal disease or age
> 35 years, radical surgery led to lower intrauterine pregnancy rate than conservative surgery (hazards ratio (HR) = 0.67 (0.50–0.91)).
In this study, conservative surgery was performed for patients with both symptomatic and nonsymptomatic ectopic pregnancy.
Two recent randomized trials compared fertility rate after con- servative and radical surgery. In the first study, 63 women were in the conservative surgery group and 66 others in the radical surgery group. There was no significant difference between the two groups in the 2-year intrauterine pregnancy rates (70 % versus 64 %, p:
nonsignificant) [19].
The second randomized trial included 446 women (215 in the conservative surgery group and 231 in the radical surgery group).
The 3-year intrauterine spontaneous pregnancy rate was 60.7 % af- ter conservative surgery and 56.2 % after radical surgery ( p: not significant) [20]. Table 21.2 shows pregnancy rates after conserva- tive versus radical surgical treatments.
P. Capmas et al.
158
Table 21.2 Spontaneous intrauterine pregnancy rate after conservative (salpingostomy) or radical surgical management (salpingectomy) StudyType of studyConservative surgeryRadical surgeryHRp n Spontaneous IUP
a rate (%)n
Spontaneous IUP
a rate (%) De Bennetot et al. [12]
Prospective observational (registry)
64676 (0.73–0.80)29967 (0.61–0.74)0.78 (0.66–0.93) Fernandez et al. [19]Randomized trial637066641.06 (0.69–1.63)0.77 Mol et al. [20]Randomized trial21560.7%23156.21.06 (0.81–1.38)0.68 Mol et al. [20]Meta analyses2782971.08 (0.86–1.36)0.52 aIUP intrauterine pregnancy, HR hazards ratio
Recurrent ectopic tubal pregnancy in the Demeter trial was 8 % after salpingostomy and 12.5 % after salpingectomy. These rates are not significantly different ( x2 = 0.003, p = 0.96) [19]. The same findings were reported in the Auvergne registry [12].
In conclusion, subsequent fertility after conservative or radical surgery for symptomatic tubal pregnancy appears to be similar.
IVF Pregnancy After Ectopic Tubal Pregnancy Treated with Methotrexate
Infertility after ectopic pregnancy is common and the patients may need to be treated with in vitro fertilization (IVF) without any de- lay. The rate of infertility after ectopic pregnancy is not specifically reported in published study. If one considers 70 % rate of intrauter- ine pregnancy and a 10–15 % recurrence rate of ectopic pregnancy, it could be around 15 %.
In a study of 66 women undergoing IVF, the authors found no differences in markers of ovarian reserve (follicle stimulating hor- mone (FSH), antral follicle count) before and after methotrexate treatment. However, a larger dose of gonadotropin was required in those after methotrexate treatment. The number of retrieved oo- cytes, quality of embryos, and pregnancy rates are comparable [21].
It appears that methotrexate does not compromise ovarian re- serve and IVF success rate in subsequent cycles. However, the higher dose of gonadotropins needed to obtain equivalent stimula- tion raises a question about altered ovarian responsiveness [22].
Further studies are needed. However, Wiser et al. found that metho- trexate treatment or salpingectomy does not affect ovarian response in the subsequent IVF cycle [23].
In conclusion, ovarian reserve and pregnancy rate after IVF are not affected by previous methotrexate injection (Fig. 21.1).
P. Capmas et al.
160
Fig. 21.1 Sonographic diagnosis of ectopic pregnancy on the left side and cor- pus luteum on the right side
Outcome
Eight months after the episode of ectopic pregnancy, the patient conceived again and an early ultrasound examination demonstrated an intrauterine pregnancy. Subsequently, she delivered a healthy male infant.