Fertility outcomes following expectant ... - Wiley Online Library

Ultrasound Obstet Gynecol 2007; 30: 988–993 Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/uog.5186

Fertility outcomes following expectant management of tubal ectopic pregnancy S. HELMY, E. SAWYER, D. OFILI-YEBOVI, J. YAZBEK, J. BEN NAGI and D. JURKOVIC Early Pregnancy and Gynaecology Assessment Unit, King’s College Hospital, London, UK

K E Y W O R D S: ectopic pregnancy; expectant management; fertility; salpingectomy

ABSTRACT Objectives To evaluate fertility outcome after the expectant management of tubal ectopic pregnancy. Methods Our dedicated early pregnancy database was searched for all women diagnosed with a tubal ectopic pregnancy between January 1999 and June 2003 who were either managed expectantly or underwent a salpingectomy. They were contacted to enquire about their ability to conceive following the ectopic pregnancy and about the outcomes of any subsequent pregnancies. Results Four hundred and forty-four women had a diagnosis of tubal ectopic pregnancy, and 173 (39%) were successfully contacted. A total of 146/173 (84.4%; 95% CI, 79–89.8%) tried for another pregnancy: 49/59 (83.1%; 95% CI, 73.4–92.6%) in the expectant management and 97/114 (85.1%; 95% CI, 78.4–91.6%) in the salpingectomy group (P > 0.05). Spontaneous intrauterine pregnancy occurred in 41/49 (83.7%; 95% CI, 73.3–94.2%) women managed expectantly and in 62/97 (63.9%; 95% CI, 54.4–73.5%) women managed surgically (odds ratio 2.89; 95% CI, 1.22–6.86%). The risk of recurrent ectopic pregnancy was not significantly different between the two management groups. Conclusions Fertility outcomes following the expectant management of tubal ectopic pregnancy are comparable to those following salpingectomy. Copyright  2007 ISUOG. Published by John Wiley & Sons, Ltd.

INTRODUCTION The effect of different management strategies on subsequent fertility following tubal ectopic pregnancy is unknown. There is some evidence to suggest that

future fertility outcomes are slightly improved following tubal conservation at surgery in comparison to salpingectomy1,2 . A recent Cochrane review3 concluded that laparoscopic surgery is the ‘gold standard’ in the majority of women, although laparoscopic salpingotomy is less successful than open salpingotomy in the elimination of tubal pregnancy owing to a higher rate of persistent trophoblast. Long-term follow-up shows that the intrauterine pregnancy rate is comparable, and the incidence of repeat ectopic pregnancy is lower after laparoscopic surgery. However, there is a group of women with ectopic pregnancy who can be managed non-surgically. One of the potential advantages of non-surgical treatment of ectopic pregnancy is the avoidance of any iatrogenic injury to the Fallopian tubes, which may decrease the risk of recurrent ectopic pregnancy and improve the chance of successful intrauterine conception. Some small studies have shown that tubal patency and future reproductive outcomes are significantly improved in women managed expectantly compared with those who underwent surgery4,5 . Expectant management is not often used in clinical practice and all studies published so far included a relatively small number of patients4 – 9 (Table 1). The aim of our study was to assess reproductive outcomes following expectant management of ectopic pregnancy in a large number of patients treated in a single center.

METHODS We searched our database for all women who had a certain ultrasound diagnosis of tubal ectopic pregnancy in our Early Pregnancy Assessment Unit between January 1999 and June 2003. Our unit serves a racially mixed inner city population with a high level of socioeconomic deprivation. All women included in the study conceived spontaneously, and were referred for assessment by their

Correspondence to: Dr E. Sawyer, Early Pregnancy and Gynaecology Assessment Unit, King’s College Hospital, London, SE5 8RX, UK (e-mail: [email protected]) Accepted: 10 July 2007

Copyright  2007 ISUOG. Published by John Wiley & Sons, Ltd.

ORIGINAL PAPER

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Table 1 Fertility after expectant management of tubal ectopic pregnancy: a review of the literature

Reference Fernandez et al. 19889 Fernandez et al.19916 Shalev et al. 19958 Zohav et al. 19967 Rantala et al. 19975 Strobelt et al. 20004 Present study

Successful expectant management ( n)

Pregnancy desired (n (%))

Unable to conceive (n (%))

Intrauterine pregnancy (n (%))

Recurrent ectopic (n (%))

Miscarriage (n (%))

9 12 28 33 30 63 59

6/9 (66.7) 9/12 (75) 24/28 (85.7) 20/33 (60.6) 24/30 (80) 34/63 (54.0) 49/59 (83.1)

NA NA NA 3/20 (15) 3/24 (12.5) NA 4/49 (8.2)

3/6 (50) 8/9 (88.9) 15/24 (62.5) 16/20 (80) 20/24 (83.3) 22/34 (64.7) 41/49 (83.7)

N/A 0/9 (0) 3/24 (12.5) 1/20 (5) 1/24 (4.2) 3/34 (8.8) 4/49 (8.2)

NA NA NA 0/20 (0) 1/24 (4.2) NA 13/49 (26.5)

NA, data not available.

general practitioners or hospital consultants because of suspected early pregnancy complications. They all had a positive urinary pregnancy test, and underwent a transvaginal ultrasound examination. The diagnosis of ectopic pregnancy was made on ultrasound scan when a well defined adnexal mass was seen separate from the uterus and the ovary containing the corpus luteum, which had typical morphological characteristics of a tubal ectopic pregnancy. Morphological features of ectopics were classified into three groups: gestational sac containing a live embryo, an empty gestational sac with or without a yolk sac, and a solid hyperechogenic swelling. Women with non-diagnostic scans were offered surgery only if they presented with severe unexplained pain, cardiovascular instability, or if there was clinical and ultrasound evidence of intraperitoneal bleeding. All other women were managed expectantly according to a previously designed protocol, which included serial human chorionic gonadotropin (hCG) and progesterone measurements until the final diagnosis was reached10 . Women with inconclusive scans (pregnancies of unknown location) and those who had an ectopic following in vitro fertilization treatment were not included in this analysis. All clinically stable women with ultrasound findings conclusive of a non-viable tubal ectopic pregnancy and an initial serum hCG measurement 1500 IU/L. All women in the expectant management group were managed on an outpatient basis with serial hCG measurements. Follow-up continued until the serum hCG declined to less than 20 IU/L or the urine pregnancy test became negative. Expectant management was discontinued if women developed increasing abdominal pain or the hCG levels showed a sustained rise on repeated measurement. All women with failed expectant management were offered surgery11 . Methotrexate was not offered to women with an increasing hCG level, because most of them were managed conservatively for a number of days and we did not think that continuing conservative management would


be appropriate. If the hCG level rose by more than 15% on two occasions, surgery was advised. Some women also complained of abdominal pain, which is a contraindication to medical treatment in our department. Surgical treatment involved laparoscopy in most cases. At laparoscopy, salpingectomy was performed using ready-made surgical ligatures (Ethicon, Johnson and Johnson Co., Cornelia, GA, USA) to tie the Fallopian tube before excision. Salpingotomy was performed by incising the Fallopian tube on the antimesenteric side using cutting diathermy. Hydrodissection was then used to separate the ectopic from the Fallopian tube. In women with a healthy contralateral tube a salpingectomy was performed in preference to salpingotomy12 . Salpingectomy was also performed in cases of rupture causing irreparable tubal damage. Indications for salpingotomy were an absent or damaged contralateral tube and patient’s request. The main indication for open surgery was evidence of cardiovascular instability. Open surgery was also considered in women with previous midline incisions, a history of severe pelvic adhesions and fibroid uterus of more than 18 weeks’ size. At open surgery the tubes were tied and divided using the traditional technique of salpingectomy1 . All women with ectopic pregnancies who had at least one Fallopian tube conserved were contacted by telephone following discharge from hospital. The interval between discharge and follow-up ranged from 24 to 66 months. Details of their past gynecological histories were checked again and they were all asked about their reproductive outcomes following ectopic pregnancy. Those women who attempted to conceive again were asked about their ability to become pregnant and the outcome of all subsequent pregnancies. Women who became pregnant on in-vitro fertilization treatment following an ectopic pregnancy were classified as being unable to conceive. Univariate and multivariate logistic regression analysis was conducted to assess the relationships between various demographic and clinical parameters and women’s ability to conceive again after an ectopic pregnancy. P < 0.05 was considered statistically significant.

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RESULTS

Table 2 Effect of maternal age and previous gynecological history on future fertility in women with ectopic pregnancies

In the period of 54 months a total of 444 women were diagnosed with tubal ectopic pregnancy; 134/444 (30.2%; 95% CI, 26–35) had successful expectant management and 310/444 (69.8%; 95% CI, 65–74) were managed surgically. In the surgical group 296/310 (95.4%; 95% CI, 93–97) had a salpingectomy and 14/310 (4.5%; 95% CI, 3–7) had a salpingotomy. We included only women who underwent salpingectomy in the final analysis. In all, 173/430 (40.2%; 95% CI, 36–45) women were contacted successfully. Of these, 95/173 (54.9%; 95% CI, 48–62) had primary surgical treatment and 78/173 (45.1%; 95% CI, 38–53) were initially managed expectantly. The success of expectant management was 59/78 (76%; 95% CI, 67–86) and a total of 59/173 (34.1%; 95% CI, 27–41) ectopic pregnancies resolved spontaneously. Some 114/173 (65.9%; 95% CI, 59–73) women had salpingectomy; 106 (93.0%; 95% CI, 88–98) had laparoscopic surgery and the remaining eight (7.0%; 95% CI, 2–12) women had a laparotomy. A total of 146/173 (84.4%; 95% CI, 79–90) women tried for another pregnancy, 49/59 (83.1%; 95% CI, 73–93) in the expectant management group and 97/114 (85.1%; 95% CI, 78.4–91.6) in the group of women treated surgically (P > 0.05) (Figure 1). In all, 119/146 (81.5%; 95% CI, 75.2–87.8%) women achieved another pregnancy. On univariate logistic regression analysis the chance of subsequent pregnancy was significantly decreased with increasing maternal age (P < 0.01) but a history of previous conceptions, pelvic infection or abdominal surgery had no effect on fertility following an ectopic pregnancy (P > 0.05) (Table 2). The mean maternal age in those managed expectantly was 30.4 years and in those managed surgically it was 30.6 years (P > 0.05) (Table 3). Women managed expectantly had a higher chance of having a spontaneous intrauterine pregnancy (83.7% vs. 63.9%; OR 2.89; 95% CI, 1.22–6.86). They also had a higher chance of a normal intrauterine pregnancy and lower risk of a

Variable

β

Maternal age* Past history of successful conception Past history of pelvic infection Previous abdominal surgery

Wald SE (β ) chi-square

P

Odds ratio

0.12 0.30

0.05 0.54

6.75 0.31

0.009 0.58

1.12 1.35

−0.15

0.60

0.06

0.80

0.86

0.22

0.47

0.22

0.64

1.25

*At the time of diagnosis of ectopic pregnancy. SE, standard error.

recurrent ectopic than those treated surgically, but these differences were not statistically significant (Table 4). The cumulative intrauterine pregnancy rates following a tubal ectopic were consistently higher in the expectant group at any time during follow-up (Figure 2).

Cumulative pregnancy rate (%)

60 50 40 30 20 10 0

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time (months)

Figure 2 Cumulative pregnancy rates following expectant ( ) management of tubal ectopic pregnancy. and surgical (

)

Total number of tubal ectopics n = 444

Salpingectomy n = 296

Lost to follow-up n = 182

Included in follow-up n = 114

Pregnancy desired n = 97

Expectant management n = 134

Salpingotomy n = 14

Included in follow-up n = 59

Lost to follow-up n = 75

No pregnancy desired n = 17

Pregnancy desired n = 49

No pregnancy desired n = 10

Figure 1 Study flow chart.



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Table 3 Comparison of demographic characteristics of women with tubal pregnancies who were managed expectantly or surgically

Characteristic Age (years, mean (range)) Nulliparity (n (%; 95% CI)) History of ectopic pregnancy (n (%; 95% CI)) History of intrauterine pregnancy (n (%; 95% CI)) History of sexually transmitted disease (n (%; 95% CI)) History of pelvic inflammatory disease (n (%; 95% CI)) History of abdominal surgery (n (%; 95% CI))

Expectant group (n = 49)

Surgical group (n = 97)

P

30.4 (19–40) 8 (16.3; 6–26.6) 9 (18.4; 6–29.2) 40 (81.6; 70.8–92.4) 6 (12.2; 3.0–21.4) 1 (2; −1.9 to 5.9) 18 (36.7; 23.2–50.2)

30.6 (16–44) 25 (25.8; 17.1–34.5) 2 (2.1; −0.8 to 5) 70 (72.2; 63.3–81.1) 15 (15.5; 8.3–22.7) 2 (2.1; −0.8 to 5.0) 12 (12.4; 5.8–19)

NS NS NS NS NS NS NS

NS, not significant. Table 4 Comparisons of future fertility and outcome of the first pregnancy following a tubal ectopic in women managed expectantly or surgically

Fertility outcome Unable to conceive (n (%; 95% CI)) Normal intrauterine pregnancy (n (%; 95% CI)) Miscarriage (n (%; 95% CI)) Recurrent ectopic (n (%; 95% CI))

Expectant (n = 49)

Salpingectomy (n = 97)

Odds ratio (95% CI)

4 (8.2; 0.4–15.6) 28 (57.1; 43.1–70.9) 13 (26.5; 16.2–40.3) 4 (8.2; 0.4–15.6)

23 (23.7; 15.5–32.5) 48 (49.5; 40–59.3) 14 (14.4; 7.1–20.9) 12 (12.4; 5.5–18.5)

0.29 (0.09–0.88) 1.36 (0.68–2.72) 2.14 (0.91–5.01) 0.62 (0.19–2.07)

Some 13/49 (26.5%; 95% CI, 14.1–38.9) women who underwent expectant management and 19/97 (19.6%; 95% CI, 11.7–27.5) who had surgery achieved a normal second pregnancy after an ectopic pregnancy (P > 0.05).

DISCUSSION The results of this study show that expectant management of ectopic pregnancies leads to future fertility outcomes that are comparable to those after salpingectomy. The rate of subsequent spontaneous intrauterine pregnancies is significantly higher in expectantly managed women and the number of recurrent ectopics tends to be smaller, though not significantly so. The rate of intrauterine pregnancies of 83.7% was similar to the findings of previously published studies, which reported intrauterine pregnancies in 65–89% of women following expectant management of tubal ectopics4 – 7 . The cumulative 3-year intrauterine pregnancy rate after salpingectomy was 46%, which was comparable to the rate of 38% published by Mol et al. in 19982 . The majority of women who were treated surgically in our study underwent salpingectomy. This was in accordance with the UK guidelines on the management of tubal ectopic pregnancy, which were valid at the time of the study12 . Only a very small number of women had salpingotomy and we are therefore unable to comment on the reproductive outcomes following tubal conservation. The recurrent ectopic rate after expectant management of 8% was broadly in agreement with the previously reported rates of 4–13%4,5,7,8 . The recurrent ectopic rate following radical surgery was 12%, which was also similar to the reported range of 6–13%2,13 – 18 . These results


are reassuring as there were concerns that prolonged retention of an ectopic trophoblast in women managed expectantly may have been detrimental to tubal function and predispose women to further ectopic pregnancies. The slightly better reproductive outcomes following expectant management could be explained by the avoidance of iatrogenic injury to the contralateral tube, which may occur during pelvic surgery to remove an ectopic pregnancy. However, this was not a randomized study and ectopics treated surgically typically presented with more severe clinical symptoms, were larger and were associated with higher hCG levels. Therefore, it is possible that better outcomes in the expectant management group may reflect the generally milder presentation of the condition in comparison to that in women who received surgical management. It is also possible that smaller non-viable ectopics, which lend themselves to expectant management, may be caused by an intrinsic pregnancy abnormality, rather than being a consequence of previous tubal damage. We do not routinely test tubal patency after ectopic pregnancy and therefore it is not possible to comment on the differences between women undergoing expectant management or surgery, in terms of the prevalence of tubal disease. Data from the literature, however, do not show a significant difference in tubal patency rates between these women19,20 . It is important to stress that tubal patency testing does not provide information about tubal function, and it is minor tubal injury, rather than obstruction, which may be of more importance in determining the rate of tubal implantation. In addition to the improved future reproductive outcomes, expectant management has many other advantages over surgical management. The treatment is


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free from any operative and anesthetic risks. None of the women with successful expectant management had been admitted to hospital, which further decreases the costs and minimizes social disruption. The main problem with expectant management is a significant failure rate11 and 24% of our patients required surgical intervention at a later date. Expectant management also compares favorably with medical treatment of ectopic pregnancy with methotrexate for a specific group of women. In our study 45% of women were initially managed expectantly with a 76% success rate. Therefore, 30% of all ectopic pregnancies seen in our unit over the study period did not require any medical intervention. This is similar to the overall success rate of single-dose methotrexate for the treatment of tubal ectopic pregnancy in previous randomized studies. Hajenius et al. reported that the success rate of a single dose of methotrexate for the treatment of tubal ectopics was 82%19 . However, only 32% of ectopics were considered suitable for medical treatment, which indicates that only 27% of the total number of women who presented with tubal ectopics during the study period would have been treated successfully with methotrexate. In another study on the efficacy of a single dose of methotrexate, 36% of women with ectopics were suitable for medical treatment with a success rate of 65%, giving a total cure rate of 23%21 . These results indicate that the contribution of a single dose of methotrexate to the successful conservative treatment of ectopics may be more limited than previously thought. Multiple-dose regimens have a higher success rate, as assessed in a meta-analysis by Barnhart et al.22 , but this may be offset against side effects and impaired quality of life, and need for emergency intervention as a result of tubal rupture. Our previous work showed that the risk of rupture and severe intra-abdominal bleeding appears to be less in women managed expectantly compared with those managed medically11,19 . Expectant management is also free from side effects, which are a common problem with medical treatment. Hajenius et al. noted that 61% of women undergoing systemic methotrexate therapy experienced side effects or complications in comparison to only 12% in the surgical group19 . Nieuwkerk et al. used standard health-related quality of life questionnaires, and found that medically treated patients had consistently more limitations in role and social functioning23 . Our study may be criticized for relatively low followup rates after ectopic pregnancy. We serve mostly an inner city population with a high proportion of recent immigrants to the UK. As a result the population is very mobile, which is a likely explanation for our inability to contact a significant proportion of women treated in our department. However, the proportions of women with successful and failed follow-up were similar in the surgically and expectantly treated groups. Therefore, it is likely that the results are representative of all women with ectopics in our population. As discussed before, our study was not randomized and therefore the observed differences must be interpreted


with caution. The success rate of expectant management of ectopic pregnancies presenting with a serum hCG < 1500 IU/L is so high that it would be almost unethical to subject these women to surgical interventions. Therefore, a randomized trial of surgery vs. expectant management, which would involve a similar group of women, is unlikely to be conducted. However, even without the potential benefits in terms of future fertility, expectant management appears to be a safe and effective treatment option that is suitable for almost one-third of women diagnosed with tubal ectopic pregnancies. Although expectant management requires prolonged follow-up and there is a significant failure rate, this is offset by the avoidance of any medical intervention, a low risk of complications and reduced costs. Surgical treatment, however, remains the safest and most effective option for symptomatic women and those presenting with live ectopics or very high serum β-hCG measurements.

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