Ectopic Pregnancy: A Clinical Casebook

21. Fertility After Tubal Ectopic Pregnancy

Perrine Capmas1, 2, 3  Jean Bouyer  and Hervé Fernandez1, 2, 3, 4  

(1)

Service de Gynécologie Obstétrique, Hôpital Bicêtre, GHU Sud, AP-HP, 78, avenue du Général Leclerc, 94276 Le Kremlin Bicêtre Cedex, France

(2)

Centre of research in Epidemiology and population health (CESP), Inserm, U1018, 94276 Le Kremlin Bicêtre, France

(3)

Univ Paris Sud, 94276 Le Kremlin Bicêtre, France

(4)

BICETRE, 78 rue du General Leclerk, 94270 Le Kremlin Bicetre, France

Perrine Capmas (Corresponding author)

Email: perrine.capmas@bct.aphp.fr

Jean Bouyer

Email: jean.bouyer@inserm.fr

Hervé Fernandez

Email: herve.fernandez@bct.aphp.fr

Keywords

Ectopic pregnancyTubal pregnancySubsequent fertilityMethotrexateSalpingostomySalpingectomy

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 pregnancy (15 mm hematosalpinx) without hemoperitoneum. The serum human chorionic gonadotropin (hCG) level was 1500 IU/l. She was then treated with a single dose of methotrexate intramuscularly (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.

b.

c.

Diagnosis and Assessment

Ectopic tubal pregnancy is still a leading cause of maternal mortality in the first trimester of pregnancy. Early diagnosis and treatment 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). Ectopic 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 reproduction 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 conservative surgery by salpingostomy. Many criteria have been used to define this group. These include the initial serum hCG level, progesterone level, tubal diameter, and hemoperitoneum [28]. Some composite scores have also been used [910]. The most commonly used criterion is the initial hCG level [11], but there has been no agreement on the cutoff level [3568].

Published data on fertility after ectopic pregnancy are mainly observational. However, prospective studies from ectopic pregnancy registries in two regions of France (Auvergne and Nord) have concluded that fertility is similar after medical treatment and conservative surgery, but lower after radical surgery [1215].

In the Auvergne registry, 1064 women were included between 1992 and 2008. The rate of subsequent fertility 2 years after conservative 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 (intramuscular 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 [1618]. 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 occurred in 36 % of cases after medical treatment and in 43 % after conservative 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 comparable [17]. On the other hand, Fernandez et al. reported that the rate of intrauterine pregnancy was 96.3 % after local methotrexate treatment (n: 27) and 62 % after conservative surgery (n: 29p < 0.05) [18]. The numbers of cases in those studies are relatively low.

A larger and multicenter randomized trial (Demeter study) involved 179 women with ectopic pregnancy treated with methotrexate or conservative surgery [19]. The subsequent spontaneous intrauterine 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.

Table 21.1

Spontaneous intrauterine pregnancy rate after medical or conservative surgical management (salpingostomy)

Study

Type of study

Medical treatment

Conservative surgery

HR

p

n

Spontaneous IUPa rate (%)

n

Spontaneous IUPa rate (%)

De Bennetot et al. [12]

Prospective observational (registry)

119

76  (0.65–0.85)

646

76  (0.73–0.80)

1.07 (0.84–1.36)

 

Dias Pereira et al. [16]

Randomized trial

34

36

40

43

0.89 (0.42–1.9)

 

Zilber et al. [17]

Randomized trial

16

81

18

83.5

 

0.99

Fernandez et al. [18]

Randomized trial

27

96.3

29

62

 

 < 0.05

Fernandez et al. [19]

Randomized trial

87

71

82

67

0.85 (0.59–1.22)

0.37

a IUP 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 Auvergne registry [12]. The study demonstrates that subsequent fertility 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 salpingostomy or salpingectomy come from the registry and the two randomized trials computed for fertility analyses.

The Auvergne registry reported a higher crude cumulative intrauterine pregnancy rate after salpingostomy (76 %) than after salpingectomy (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 conservative 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 % after conservative surgery and 56.2 % after radical surgery (p: not significant) [20]. Table 21.2 shows pregnancy rates after conservative versus radical surgical treatments .

Table 21.2

Spontaneous intrauterine pregnancy rate after conservative (salpingostomy) or radical surgical management (salpingectomy)

Study

Type of study

Conservative surgery

Radical surgery

HR

p

n

Spontaneous IUPa rate (%)

n

Spontaneous IUPa rate (%)

De Bennetot et al. [12]

Prospective observational (registry)

646

76  (0.73–0.80)

299

67  (0.61–0.74)

0.78 (0.66–0.93)

 

Fernandez et al. [19]

Randomized trial

63

70

66

64

1.06 (0.69–1.63)

0.77

Mol et al. [20]

Randomized trial

215

60.7%

231

56.2

1.06 (0.81–1.38)

0.68

Mol et al. [20]

Meta analyses

278

 

297

 

1.08 (0.86–1.36)

0.52

a IUP 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 delay. The rate of infertility after ectopic pregnancy is not specifically reported in published study. If one considers 70 % rate of intrauterine 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 hormone (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 oocytes, quality of embryos, and pregnancy rates are comparable [21].

It appears that methotrexate does not compromise ovarian reserve and IVF success rate in subsequent cycles. However, the higher dose of gonadotropins needed to obtain equivalent stimulation raises a question about altered ovarian responsiveness [22]. Further studies are needed. However, Wiser et al. found that methotrexate 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).

A321655_1_En_21_Fig1_HTML.jpg

Fig. 21.1

Sonographic diagnosis of ectopic pregnancy on the left side and corpus 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.

Pearls/Pitfalls

·               There is no significant difference in subsequent fertility between medical management and conservative surgery in early and asymptomatic tubal ectopic pregnancy. Recurrence rates are also similar.

·               There is no difference in subsequent fertility between salpingostomy and salpingectomy in patients with symptomatic tubal ectopic pregnancy. Recurrence rates are also similar.

·               Because of concerns about fertility, women with at least one previous ectopic pregnancy should be directed to IVF after 1 year without pregnancy.

References

1.

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2.

Bixby S, Tello R, Kuligowska E. Presence of a yolk sac on transvaginal sonography is the most reliable predictor of single-dose methotrexate treatment failure in ectopic pregnancy. J Ultrasound Med. 2005;24(5):591–8.PubMed

3.

da Costa Soares R, Elito J Jr., Camano L. Increment in beta-hCG in the 48-h period prior to treatment: a new variable predictive of therapeutic success in the treatment of ectopic pregnancy with methotrexate. Arch Gynecol Obstet. 2008;278(4):319–24.CrossRefPubMed

4.

Dilbaz S, Caliskan E, Dilbaz B, Degirmenci O, Haberal A. Predictors of methotrexate treatment failure in ectopic pregnancy. J Reprod Med. 2006;51(2):87–93.PubMed

5.

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(3):481–4.CrossRefPubMed

6.

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7.

Nazac A, Gervaise A, Bouyer J, de Tayrac R, Capella-Allouc S, Fernandez H. Predictors of success in methotrexate treatment of women with unruptured tubal pregnancies. Ultrasound Obstet Gynecol. 2003;21(2):181–5.CrossRefPubMed

8.

Nowak-Markwitz E, Michalak M, Olejnik M, Spaczynski M. Cutoff value of human chorionic gonadotropin in relation to the number of methotrexate cycles in the successful treatment of ectopic pregnancy. Fertil Steril. 2009;92(4):1203–7.CrossRefPubMed

9.

Elito J Jr., Reichmann AP, Uchiyama MN, Camano L. Predictive score for the systemic treatment of unruptured ectopic pregnancy with a single dose of methotrexate. Int J Gynaecol Obstet: Off Organ Int Fed Gynaecol Obstet. 1999;67(2):75–9.CrossRef

10.

Fernandez H, Lelaidier C, Thouvenez V, Frydman R. The use of a pretherapeutic, predictive score to determine inclusion criteria for the non-surgical treatment of ectopic pregnancy. Hum Reprod. 1991;6(7):995–8.PubMed

11.

Lipscomb GH, McCord ML, Stovall TG, Huff G, Portera SG, Ling FW. Predictors of success of methotrexate treatment in women with tubal ectopic pregnancies. New Engl J Med. 1999;341(26):1974–8.CrossRefPubMed

12.

de Bennetot M, Rabischong B, Aublet-Cuvelier B, Belard F, Fernandez H, Bouyer J, et al. Fertility after tubal ectopic pregnancy: results of a population-based study. Fertil Steril. 2012;98(5):1271–6; e1–3.CrossRefPubMed

13.

Allonier C, Ego A, Gerbaud L, Job-Spira N, Subtil D, Bouyer J. Comparison of fertility rates after ectopic pregnancy in Auvergne and Lille regions. J Gynecol Obstet Biol Reprod. 2003;32(5):439–46.

14.

Bouyer J, Job-Spira N, Pouly JL, Coste J, Germain E, Fernandez H. Fertility following radical, conservative-surgical or medical treatment for tubal pregnancy: a population-based study. BJOG. 2000;107(6):714–21.CrossRefPubMed

15.

Bouyer J, Fernandez H, Coste J, Pouly JL, Job-Spira N. Fertility after ectopic pregnancy: 10-year results in the Auvergne Registry. J Gynecol Obstet Biol Reprod. 2003;32(5):431–8.

16.

Dias Pereira G, Hajenius PJ, Mol BW, Ankum WM, Hemrika DJ, Bossuyt PM, et al. Fertility outcome after systemic methotrexate and laparoscopic salpingostomy for tubal pregnancy. Lancet. 1999;353(9154):724–5.CrossRefPubMed

17.

Zilber U, Pansky M, Bukovsky I, Golan A. Laparoscopic salpingostomy versus laparoscopic local methotrexate injection in the management of unruptured ectopic gestation. Am J Obstet Gynecol. 1996;175(3 Pt 1):600–2.CrossRefPubMed

18.

Fernandez H, Yves Vincent SC, Pauthier S, Audibert F, Frydman R. Randomized trial of conservative laparoscopic treatment and methotrexate administration in ectopic pregnancy and subsequent fertility. Hum Reprod. 1998;13(11):3239–43.CrossRefPubMed

19.

Fernandez H, Capmas P, Lucot JP, Resch B, Panel P, Bouyer J. Fertility after ectopic pregnancy: the DEMETER randomized trial. Hum Reprod. 2013;28(5):1247–53.CrossRefPubMed

20.

Mol F, van Mello NM, Strandell A, Strandell K, Jurkovic D, Ross J, et al. Salpingotomy versus salpingectomy in women with tubal pregnancy (ESEP study): an open-label, multicentre, randomised controlled trial. Lancet. 2014.

21.

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(6):1590–3.CrossRefPubMed

22.

Xiao C, Dahan MH. The effect of methotrexate injection for treatment of an ectopic pregnancy on ovarian reserve. Fertil Steril. 2014;101(4):e23.CrossRefPubMed

23.

Wiser A, Gilbert A, Nahum R, Orvieto R, Haas J, Hourvitz A, Weissman A, Younes G, Dirnfeld M, Hershko A, Shulman A, Tsafrir A, Holzer H, Shalom-Paz E, Tulandi T. Effects of treatment of ectopic pregnancy with methotrexate or salpingectomy on subsequent in vitro fertilization cycle. Reprod BioMed 2013;26:449–53.CrossRef


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