Surgical Outcomes and Trends in Incidence of Ectopic Pregnancy.

Ectopic pregnancy (EP) occurs in 1%–2% of all pregnancies[ 1 ] and is a disease that is not infrequently encountered in daily clinical care or in emergency medical care. In recent years, high-resolution transvaginal ultrasonography and highly sensitive serum human chorionic gonadotropin (s-hCG) tests have enabled earlier and accurate diagnosis in many cases of EP, but there are still cases of pregnancy of unknown location (PUL) that are difficult to differentiate from normal early pregnancy or intrauterine abortion,[ 1 2 ] and cases of severe conditions such as hemorrhagic shock. We accumulated data of surgically treated cases of EP since 2002,[ 3 4 5 ] and in this article, we reported 259 cases of EP during the 20-year period, detailing the surgical technique, site of pregnancy, and amount of blood loss, and discussed the differential diagnosis of preoperative PUL based on evidence from recent literature and medical practice guidelines. We also discussed the decreasing trend in the occurrence of EP based on the results of epidemiological studies of risk factors.

The total number of surgical cases of EP during the 20-year period from January 2002 to December 2021 was 259. The annual trends in the number of surgical cases and details of the surgical techniques (laparoscopic or laparotomy) are shown in Figure 2a . The breakdown of surgical procedures was as follows: 4 (1.54%) were laparotomy, 5 (1.93%) were converted from laparoscopy to laparotomy, and 250 (96.5%) were laparoscopic. From 2006 to 2018, laparoscopic surgery was performed in all EP cases, but there was one case in which laparotomy was opted for in 2019. This was a case of ovarian pregnancy (OP) with intra-abdominal bleeding (approximately 1000 mL) at 5 weeks and 1 day of gestation. The s-hCG level was 2058 IU/L. The possibility of normal intrauterine early pregnancy and ovarian bleeding could not be ruled out, and the patient wanted to have a baby, so the laparotomy under spinal anesthesia was selected for the patient. (a) Annual trends of the number of surgeries and procedures for ectopic pregnancy (EP). (b) Annual trends of the number of gynecological surgeries and the rate of EP at our hospital. EP: Ectopic pregnancy The number and percentage of pregnancies by implantation site are shown in Table 1a . TPs accounted for 90.7%, interstitial pregnancies (IPs) for 5.0%, OPs for 2.7%, and peritoneal pregnancies (PP) for 1.5%. There was one case of cervical pregnancy that could be treated with medical treatment, but there were no cases of cesarean scar pregnancies or heterotopic pregnancies. The breakdown of surgical procedure for TP was as follows: salpingectomy in 140 cases (59.6%), linear incision of the fallopian tubes (salpingostomy) in 93 cases (39.6%), and other (removal of villi and washing) in 2 cases. IP is defined as an EP implanted in the tubal interstitial portion where it traverses through the uterine muscular wall to enter the cavity, and surgical management could be carried out with either cornual resection or cornuostomy.[ 13 ] The procedures used in this study for the 13 IPs were cornual resection in 7 cases and cornuostomy in 6 cases. The details of 13 IP, 7 OP, and 4 PP cases are shown in Table 2 . IP had more cases with previous EP, higher hCG levels, less bleeding, and fewer symptomes than pregnancies at other sites, with significant differences in statistical studies.[ 5 ] The anatomical characteristics of the interstitial portion are said to be relatively resistant to rupture and prone to prolonged pregnancy, and the fact that there were no cases of rupture at our hospital may have contributed to this result. Number and percentage of ectopic pregnancy surgery cases by site of occurrence and intraoperative blood loss Details of EP in unusual sites hCG: Human chorionic gonadotropin, GS: Gestational sac, FHM: Fetal heart movement, EP: Ectopic pregnancy, Appe: Appendectomy, CS: Cesarean section, NA: Not avaliable The number and percentage of cases by intraoperative blood loss are shown in Table 1b . 48.3% of cases were <100 mL, 85.0% were 2000 mL. The highest amount of blood loss during the study period was in a case with 2800 mL of intraoperative bleeding due to a ruptured TP at 11-week gestation.[ 4 ] The other case with blood loss exceeding 2000 mL was a patient with a 7-week gestation, s-hCG level of 1914 IU/L, and ruptured TP during follow-up after D and C with a diagnosis of PUL, with a blood loss of 2.720 mL. Both cases could have been treated by laparoscopic salpingectomy. The details of cases with blood loss ≥500 mL since 2011 are shown in Table 3 . All patients with preoperative shock index (SI) >1 had bleeding of 1300 mL or more, but even in patients with bleeding volume ≥1500 mL, three of seven patients had SI <1. Statistical examination revealed no significant difference between the amount of blood loss and vital sign (systolic blood presure and shock index), and a singificant difference between the amount of bloodloss and preoperative hemoglobin level.[ 4 ] In EP, bleeding often progresses slowly, and vital sign seems to be less variable for the amount of blood loss.[ 4 ] Details of EP cases with intraoperative blood loss≥500 ml (Study of cases since 2011) SBP: Systolic blood pressure, DBP: Diastolic blood pressure, Hb: Hemoglobin (g/dL), D1: Postoperative day 1, NA: Not available, OP: Ovarian pregnancy, PP: Peritoneal pregnancy, TP-i: Pregnancy of isthmus, TP-a: Pregnancy of ampulla, CRC: Concentrated red blood cell transfusion The results of the prevalence of the main risk factors in the 114 EP cases from 2011 to 2022 were as follows. The rate of chlamydia antigen positivity was 5.4% (4 of 74), the rate of infertile patients was 10.5% (12 of 114), the rate of smokers and previous smokers was 30.0% (34 of 113) and 10.6% (12 of 113), respectively, and the rate of previous EP cases was 8.8% (10 of 114). Annual trends of the number of EP surgeries, number of gynecologic surgeries, and the rate of EP are shown in Figure 2a and b . The annual trend in the number of EP at our hospital seemed to show a downward trend in recent years [ Figure 2a ]. The rate of EP surgeries to all gynecologic surgeries had decreased significantly in recent years [ Figure 2b ].[ 3 ] The results of the survey of the four hospitals in Fukushima City also showed an overall downward trend in the number of EP surgeries as a whole, similar to the results of our hospital.[ 3 ] Furthermore, the results of the website survey on the number of chlamydial and gonococcal infections among women, the smoking rate among women aged 20–39 years, the incidence of EP by ART, and the number of births in Japan and Fukushima City all showed a downward trend in recent years [ Figure 3a - d ]. Risk factors for ectopic pregnancy and annual number of births. (a) Ministry of Health, Labour and Welfare (MHLW), Sexually Transmitted Diseases.[ 6 ] (b) MHLW, National Health and Nutrition Survey, MHLW.[ 7 ] (c) Data from ART Online Registry Data Book.[ 8 ] (d) MHLW, Vital Statistics, cited from the official Fukushima City website.[ 9 10 ] ART: Assisted reproductive technology

For an accurate diagnosis of EP, especially in PUL, it is important to set and evaluate discriminatory and serial values for s-hCG based on the latest evidence. The results of epidemiological surveys in Japan confirmed that many factors involved in the occurrence of EP, such as the number of births, the number of cases of chlamydia infection, smoking rates, and the incidence of EP in ART, are changing in the direction of decreasing the occurrence of EP. However, we will continue to pay attention to the trends of factors involved in the increase of EP occurrence, such as endometriosis and the aging of pregnancy; we will continue to focus on trends in factors involved in the increased incidence of EP, new factors involved in EP development, as well as the results of future epidemiological studies on the incidence of EP. All data generated or analyzed during this study are included in this published article. Nil. There are no conflicts of interest.

EP can be treated by surgical, medical, or expectant treatments, the choice of which is determined by the patient’s symptoms, general condition, site of pregnancy, mass diameter, s-hCG level, and presence of a fetal heartbeat.[ 2 7 ] In a recent study involving 460 EPs, the success rate of medical treatment was reported to be 90.2%.[ 14 ] In our hospital, surgical treatment was selected as the first choice for initial treatment, and laparoscopic surgery was currently selected in most cases (96.5%), including those with massive bleeding, in consideration of the minimally invasive nature of laparoscopic surgery. Although there are nolarage-scale stsudies on the incidence of EP in Japan, a larage-scale survey conducted in 14 states in the United Steges from 2004 to 2008 reported an incidence of EP of 1.40% of all preganacies, with an incidence rate of 2.3 per 1000 women per year.[ 15 ] The incidence of EP is also known to increase in infertile patients, especially with ART.[ 16 17 ] In cases of preoperative PUL, the differential diagnosis between normal early pregnancy, intrauterine abortion, and EP was made according to the algorithm shown in Figure 1 , using the s-hCG level (discriminatory or serial) as an indicator. Until recently, we have used 2000 IU/L as the discriminatory value for s-hCG, but recently, there have been reports recommending higher discriminatory values,[ 6 ] so we try to make a more accurate diagnosis by referring to these reports. In normal intrauterine pregnancies, GS can usually be confirmed by transvaginal ultrasonography if the s-hCG level is 1500–2000 IU/L or higher.[ 2 18 ] However, there are some cases in which GS cannot be confirmed even if the s-hCG level exceeds 2000 IU/L, even in normal pregnancies, so caution is required.[ 2 6 19 ] It may not be appropriate to easily initiate treatment with s-hCG ≥2000 IU/L without GS. Connolly et al . reported that in 366 normal pregnancies, GS was confirmed in 99% at 3510 IU/L.[ 6 ] Since the most important thing is to ensure that a normal early pregnancy is ruled out before beginning treatment, it is important to look at serial s-hCG levels for a more accurate diagnosis if the patient has no symptoms and is amenable to follow-up. Barnhart et al . reporeted the serial s-hCG levels in 287 cases (only those with initial s-hCG<5000 IU/L) in which the posibilty of EP could not be ruled out at the time of initial examination but were later diagnosed as normal pregnancies. The elevation rates of s-hCG (minimum, mean, and maximum) were 24%, 50%, and 81% at 1 day and 53%, 124%, and 328% at 2 days, respectively, indicating that normal pregnancy could likely be excluded in cases that did not meet these elevation rates (when the elevation rate was less than the minimum value).[ 20 ] It should also be noted that if the patient was in multiple pregnancy, GS may not be confirmed even at >2000 IU/L, because s-hCG levels are higher in multiple pregnancies than in singleton pregnancies.[ 21 ] S-hCG levels are useful in diagnosing PUL but are not a predictor of risk for tubal rupture or massive bleeding. There have been case reports of tubal rupture and hemorrhagic shock with negative pregnancy test and s-hCG levels below sensitivity,[ 3 22 ] so caution is required. Laparoscopic surgery is clearly less invasive than laparotomy and is the gold standard for the treatment of EP.[ 7 ] Although there is some debate as to whether laparoscopic surgery is indicated when the patient’s general condition has deteriorated due to massive bleeding, at our hospital, laparoscopic surgery is the first choice based on the descriptions in the Guidelines for Obstetrics and Gynecology Treatment (Obstetrics Edition 2020)[ 2 ] and Guidelines for Endoscopic Surgery in Obstetrics and Gynecology (2019 Edition).[ 7 ] Although the selection criteria for laparoscopic surgery may vary from institution to institution, important factors in the selection of laparoscopic surgery in such cases with massive blood loss include stabilization of vital signs before surgery, preparation for blood transfusion, preparation for conversion to laparotomy, intraoperative management by a skilled anesthesiologist, and surgery performed by a skilled surgeon with extensive experience in laparoscopy.[ 4 23 ] In cases where these conditions are not met, or in cases where laparoscopic surgery is expected to be difficult due to severe obesity or suspected severe adhesions, or in cases where the surgeon has difficulty performing laparoscopic surgery, the patient should be performed by laparotomy or promptly converted to laparotomy, without being wedded to laparoscopic surgery. It is important to select an appropriate surgical technique that can complete hemostasis more quickly and safely, taking into consideration the facilities and the skills of anesthesiologists and surgeons at each facility.[ 3 4 ] The main risk factors for EP are listed in some articles.[ 1 24 ] It is well known that a history of EP is the most important of these factors, and pelvic inflammatory disease and history of induced abortion also were reported to be the most important etiological factors.[ 14 ] In our study, the percentage of infertility cases and previous EP cases was about 10%, but the percentage of smokers was 40.6% if previous smokers were included, which was considerably higher than the smoking rate among women in general (20–39 years old) shown in Figure 3b . Gaskins et al . reported a 1.73-fold increase in EP occurrence in smokers in their examination of risk factors in 411 EP patients.[ 24 ] Our results reaffirm the importance of smoking as a risk factor for the occurrence of EP. It is speculated that factors that contribute to the development of TP include the following: inflammation in the fallopian tubes caused by sexually transmitted diseases (especially chlamydial infection) and smoking, which results in contraction of the fallopian tube smooth muscle and disruption of ciliary movement of the fallopian tube epithelium, thereby disrupting intrafallopian transport of fertilized eggs, and inflammation in the fallopian tubes and arrested embryos that promote the expression of various implantation inducing factors and change the environment in the fallopian tubes to be suitable for implantation.[ 24 25 ] It is also well known that the risk of EP is increased in infertile patients, especially in pregnancies with ART,[ 16 17 ] but the incidence of EP with ART has been declining in recent years, and changes in ART techniques are a major factor in this trend. Nowadays, a single frozen-thawed blastocyst transfer has become mainstream, and changes in these techniques have led to improvements in ART success rates (pregnancy rates and live birth rates) and a decrease in EP incidence rates.[ 16 17 ] Figure 2b shows that despite the increasing trend in total gynecologic surgeries in the past 20 years, the percentage of EP surgeries in the past 10 years showed a significant downward trend compared to earlier years at our hospital.[ 3 ] Since the number of EP cases with medical treatment throughout this period is limited, it can be said that the overall number of EP occurrences is decreasing. The approximate number of EP surgeries in Fukushima City as a whole surveyed in the questionnaire also showed a downward trend similar to that of our hospital.[ 3 ] Although there are no reports of large-scale surveys in Japan on the incidence of EP, a long-term survey in the United States from 2000 to 2008 in the three states of Illinois, California, and New York reported a downward trend in the incidence of EP, and the possibility that this is the effects of prevention of sexually transmitted diseases, antismoking education, etc., is discussed in the discussion.[ 15 ] Nationally, the number of births has been declining in recent years [ Figure 3d ], and naturally, it can be assumed that the total number of pregnancies also declining, which is one reason for the decline in the number of EP occurrences. Epidemiological study results show that the number of chlamydia infections [ Figure 3a ] and smoking rates [ Figure 3b ], which are cited as EP risk factors, have both shown a downward trend in recent years, and furthermore, the incidence of EP in ART pregnancies has also shown a steady downward trend in recent years in Japan [ Figure 3c ]. It is speculated that increases or decreases in the incidence of EP will vary primarily with trends in the number of pregnancies and risk factors. In future, even if the above factors are maintained at low levels, there is a possibility that the EP incidence will shift toward an increasing trend due to the influence of other factors. In particular, a significant increase in EP incidence has been reported in patients with endometriosis, which has been on a marked increase in recent years,[ 26 27 ] and there is a concern that this could be a factor in future increase in EP.

We evaluated the number of cases, surgical procedures, pregnancy sites, and blood loss in cases in which surgery was performed with a diagnosis or suspicion of EP, and the diagnosis of EP was confirmed at Fukushima Red Cross Hospital from 2002 to 2021. This retrospective study was approved by the Institutional Review Broad of our hospital (approval number: 2022-65). Informed consent (IC) for future use of medical records in scientific researches was obtained from all women at the time of admission. EP was diagnosed when the pregnancy test was positive, and a gestational sac (GS) or fetus is found outside the endometrium. If the pregnancy test was positive and no GS was found in the uterine cavity, a diagnostic laparoscopy was performed if a hematoma was found in the adnexal region, a moderate or large amount of bloody ascites was found in the abdominal cavity, or the patient had acute abdomen, to confirm the diagnosis of EP and to treat the patient once a definitive diagnosis of EP was obtained. In cases with no findings or symptoms suspicious of EP (preoperative PUL), s-hCG levels (discriminatory or serial) were evaluated according to the algorithm for EP diagnosis shown in Figure 1 . Dilation and curettage (D and C) was performed when necessary to make a differential diagnosis of EP or intrauterine abortion. When an intrauterine abortion was ruled out and the possibility of EP was high, diagnosis and treatment by laparoscopy were performed. As the discriminatory value of s-hCG, although 2000 IU/L was conventionally adopted, the diagnosis was made based on the reports recommending a higher standard value (3510 IU/L)[ 6 ] in recent cases. If the case was preoperative PUL and the s-hCG level was under discriminatory value, the diagnosis was made based on the serial changes in s-hCG levels and treated [ Figure 1 ]. Algorithm for evaluation of a patient with a suspected ectopic pregnancy (PUL*). *PUL: Pregnancy of unknown location, **s-hCG: Serum human chorionic gonadotropin, ***D and C: Dilation and curettage, EP: Ectopic pregnancy If the diagnosis of EP was comfirmed or EP was strongly suspected during the diagnostic process of PUL [ Figure 1 ], surgical treatment being recomended as th first choice of therapoitic intervention in our clinic. The choice of laparoscopic surgery or laparotomy was made in consideration of the patient’s condition, wishes, etc. Basically, laparoscopic surgery was chosen as the first choice based on our experience at our hospital. There are two main surgical methods for tubal pregnancy (TP): conservative surgery (salpingostomy) and radical surgery (salpingectomy). The decision of the surgical method is based on the indication conditions for fallopian tube preservation surgery in the Guidelines for Obstetric and Gynecologic Endoscopic Surgery,[ 7 ] namely, (1) desire to preserve fertility, (2) lesion size <5 cm, (3) s-hCG ≤10,000 IU/L, (4) first fallopian tube pregnancy, and (5) unruptured fallopian tubes. After IC was obtained regarding postoperative tubal obstruction, persistent EP, and the possibility of EP recurrence in the next pregnancy, salpingostomy was selected for those patients who consented. Patients undergoing salpingostomy were also treated with 20 mg of methotrexate injection into the mesentery of the fallopian tubes under IC. In all cases where surgical treatment was performed, postoperative histopathology confirmed the presence of chorionic villi and identified the site of pregnancy. Because we recommend surgical treatment as the first-line treatment for EP, the number of patients who underwent medical or expectant treatment was limited and thus excluded them from this study. In 114 EP surgical cases since 2011, we investigated the proportion of chlamydia antigen-positive, infertile, smokers, previous smokers, and previous EP cases. Among the risk factors associated with the occurrence of EP,[ 1 ] we investigated the annual trends of sexually transmitted diseases ( Chlamydia trachomatis and gonococcal infection), smoking, and assisted reproductive technology (ART) treatment, which can be investigated based on the Ministry of Health, Labour and Welfare (MHLW) Sexually Transmitted Disease Report Count,[ 8 ] MHLW National Health and Nutrition Survey,[ 9 ] and ART Online Registry Data Book.[ 10 ] We also investigated the number of births in Fukushima City from the official Fukushima City website.[ 11 ] In addition, we investigated the number of births in Japan from the Vital Statistics of the MHLW.[ 12 ] The Mann–Whitney U -test was used to test for significant differences, with P < 0.05 indicating a significant difference.