Links To And Excerpts From “Overview of ectopic pregnancy diagnosis, management, and innovation”

Today, I review, link to, and excerpt from Overview of ectopic pregnancy diagnosis, management, and innovation [PubMed Abstract] [Full-Text HTML] [Full-Text PDF]. Womens Health (Lond). 2023 Jan-Dec:19:17455057231160349. doi: 10.1177/17455057231160349. Kellie Mullany, Madeline Minnecihttps, Ryan Monjazebhttps, and Olivia C. Coiadohttps.

All that follows is from the above resource.


Ectopic pregnancies are the leading cause of maternal mortality in the first trimester, with an incidence of 5%–10% of all pregnancy-related deaths. Diagnosis of ectopic pregnancies is difficult due to clinical mimics and non-specific symptoms of abdominal pain and vaginal bleeding. The current standard for ectopic pregnancy diagnosis includes ultrasound imaging and β-human chorionic gonadotropin (β-hCG) monitoring. In addition to β-hCG, serum markers are being explored as a potential for diagnosis, with activin-AB and pregnancy-associated plasma protein A specifically showing promise. Other diagnostic methods include endometrial sampling, with dilation and curettage showing the highest specificity; however, frozen section reduces the diagnostic timeline which may improve outcomes. Treatment options for confirmed ectopic pregnancies include medical, surgical, and expectant management. Chosen treatment methodology is based on β-hCG levels, hematologic stability, and risk of ectopic pregnancy rupture. Current innovations in ectopic pregnancy management aim to preserve fertility and include laparoscopic partial tubal resection with end-to-end anastomosis and uterine artery embolization with intrauterine infusion of methotrexate. Psychological interventions to improve patient mental health surrounding ectopic pregnancy diagnosis and treatment are also valuable innovations. This literature review aims to bring light to current ectopic pregnancy diagnostics, treatments, and future directions.
ectopic pregnancyectopic pregnancy diagnosisectopic pregnancy innovationectopic pregnancy treatmentglobal women’s healthmaternal healthpublic healthreproductive healthRoe v. Wadewomen’s health

1Carle Illinois College of Medicine, University of Illinois Urbana Champaign, Urbana, IL, USA
2Department of Biomedical and Translational Sciences, Carle Illinois College of Medicine and Department of Bioengineering, University of Illinois Urbana Champaign, Urbana, IL, USA


Ectopic pregnancy (EP) ruptures are the leading cause of maternal mortality within the first trimester of pregnancy with a rate of 9%–14% and an incidence of 5%–10% of all pregnancy-related deaths.1 A gestational sac (GS) that implants in a location that is not the uterus is defined as an EP. Women with an EP may have nonspecific symptoms such as lower abdominal pain and vaginal bleeding, often presenting clinically similar to appendicitis, urinary calculi, early pregnancy loss, or trauma.2 Women with this presentation in the first trimester have an EP prevalence in emergency departments as high as 18%, which can be easily misdiagnosed as the previously described clinical mimics.3 Descriptions of EPs and their prevalence are found in Table 1.
Tubal EPs are the most common type and have high maternal morbidity and mortality when ruptured.1 The rate of ruptured EPs is approximately 15% in Western countries, with a retrospective study showing an increased rupture rate during the COVID-19 pandemic.6 Heterotopic EPs are particularly complex, and their incidence is increasing due to a correlation with assisted reproductive technologies (ART), with an incidence of 1/100 pregnancies with in vitro fertilization (IVF) and 1/7000 pregnancies from ART with ovulation induction.1 Increasing rates of IVF are correlated with rising reports of EPs among those individuals. The EP rate among IVF pregnancies is 2.1%–8.6% after embryo transfer, in comparison to 2% in natural conceptions.7 Furthermore, the World Health Organization (WHO) notes an increasing rate of cesarean sections, currently reported as 21% of childbirths globally, which may in turn increase the rate of cesarean scar EPs (CSPs) over time.8 The current standard for diagnostics includes ultrasound (US) imaging—transvaginal (TVUS) or transabdominal (TAUS)—and β-human chorionic gonadotropin (β-hCG) level monitoring. Earlier and more specific EP diagnosis can help reduce maternal mortality rates. Current experimental studies are identifying biomarkers and endometrial sampling techniques that may be useful for more effective diagnostics. Once an EP is diagnosed, treatment can consist of medical, surgical, or expectant management, with innovative emphasis on conservation of fertility.

Research methods

This analysis examines and reviews literature involving the diagnosis and treatment of EPs from 2011 to 2022. Using the online PubMed search engine and Google, this review compiles 64 literature articles. While compiling literature for this review, several methodologies were followed as outlined in Figure 1.

At risk populations

Half of patients diagnosed with an EP have no known risk factors.2 Risk factors include prior EP, damage to fallopian tubes, prior pelvic surgery, complications from ascending pelvic infection, prior fallopian tube surgery or pathology, infertility, smoking, age greater than 35 years old, pelvic inflammatory disease, endometriosis, variant reproductive system anatomy, pregnancy that occurs with an intrauterine device (IUD) in place, or use of ART.2,3,10,11
Individuals with IUDs are at lower risk for EP than individuals who do not use contraception; however, 53% of pregnancies that occur in patients with IUDs are ectopic.3 Patients with a history of one prior EP have a 10% risk of subsequent EP recurrence while those with a history of two or more prior EPS have a risk greater than 25%.3 Specific risk factors associated with ART include increased number of embryos transferred, fresh instead of cryo-thawed embryo transfers, and cleavage-stage (Day 3) instead of blastocyst (Day 5) embryo transfers.11
Oral contraceptive use, prior termination of pregnancy, emergency contraception failure, cesarean delivery, and loss of pregnancy have not been found to have any significant association with increased risk of EP.3

Diagnostic methods

Current diagnostic methods for EP rely on serum β-hCG levels in correlation with TVUS or TAUS findings. TVUS has been shown to be more accurate and sensitive compared to TAUS in the diagnosis of early EP.12 Specifically, three-dimensional TVUS combined with color Doppler US was shown to be more effective than conventional 3D-US for the diagnosis of early CSP.13 Imaging mimics make EPs difficult to diagnose; however, awareness of differentiating features on US allows for more effective diagnosis, as summarized in Table 2.
β-hCG trends are used in conjunction with US to determine EP diagnosis. A patient with a β-hCG level > 2000 mIU/mL with no sign of intrauterine pregnancy (IUP) is highly suspicious of EP.1 β-hCG level is monitored to determine a miscarriage or fetal development pattern. Viable IUPs are 99% likely to have a 49% increase in β-hCG levels over 48 h when initial levels were < 1500 mIU/mL.2 Decreasing levels or a slower rate is suggestive of miscarriage or EP, with a decrease of 21% or greater most likely a failed IUP.2 Overall, the complexity of diagnosis depends on the type of EP.

Experimental markers

In patients with a pregnancy of unknown location (PUL), 50%–70% are found to have either an EP or miscarriage, while the remaining 30% may have a normal IUP.14 Serial β-hCG levels are monitored to determine pregnancy location and prognosis. A rise less than 35% in 2 days suggests EP with an accuracy of 80.2%.14
Outside of β-hCG, experimental markers are being researched for potential use in diagnostics; however, they are not traditionally used in clinical settings. Such markers include inhibin A, activins, pregnancy-associated plasma protein A (PAPP-A), A disintegrin and metalloprotease-12 (ADAM-12), vascular endothelial growth factor (VEGF), and messenger and micro-RNA. Table 3 summarizes the efficacy of markers in various studies.
There is limited literature on the efficacy of the biomarkers described above. For example, ADAM-12 was shown to have conflicting value in diagnostics.16,17 As such, further studies should be conducted to confirm diagnostic value.

Exploratory diagnostics

In addition to experimental markers, endometrial sampling is being explored as a new format for EP diagnosis. Endometrial sampling allows for differentiation of failed IUPs from EPs, thus allowing patients to avoid unnecessary methotrexate (MTX) treatment.11 EP diagnostic assumption without dilation and curettage (D&C) endometrial sampling resulted in up to 40% of patients being treated for falsely diagnosed EPs.9 Failed IUPs are confirmed by presence of villi on endometrial sampling and/or a 15%–20% decline of β-hCG the day following the procedure.14 Endometrial sampling can be completed using endometrial biopsy pipelles, D&C, Karman cannula aspiration, or frozen sections. Table 4 summarizes the sensitivity and specificity of exploratory diagnostic tools as described below.
D&C is found to have higher sensitivity rates for EP diagnosis in comparison to endometrial biopsy pipelles; however, both procedures are limited in accuracy and further studies are needed to confirm diagnostic value.24 Frozen section technique is performed on endometrial material shortly after curettage and decreases the time needed to disprove EP diagnosis.25 Of 106 women who underwent frozen section technique, nine patients with IUP were falsely started on MTX therapy and three patients with EPs were incorrectly diagnosed with IUP and discharged.25 Concurrent methods for diagnosis are necessary to avoid unwanted pregnancy termination and missed EPs. Karman cannula aspiration of endometrium allowed 2/3 of women to avoid EP treatment and showed faster recovery times of 12.6 days for IUP when compared to 26.3 days for patients treated with MTX.27 Pipelle sampling was found to have higher sensitivity in patients with β-hCG ⩽ 2000 mIU/mL, suggesting selective diagnostic potential.24
Review of Table 4 indicates that all methods of endometrial sampling have > 95% specificity for diagnosis; however, D&C demonstrates the highest sensitivity, thus confirming it as the most effective protocol.
EP diagnostics are complex and difficult to determine early in the pregnancy. Current methods of US imaging alongside β-hCG are effective in diagnosis, however serum biomarkers and endometrial sampling show promise as future diagnostic methods. Further studies and investigations can help to confirm their value in early EP diagnostics, in hopes of diminishing the maternal mortality rate.


Once diagnosis of EP is confirmed, treatment can take a conservative or aggressive approach depending on EP location, pregnancy timeline, and GS size. There are three different approaches to the treatment of EPs—medical, surgical, and expectant management—which are based on the type of EP, as seen in Table 5.
Table 5-Summary of Treatment Recommendations for Various Types of Ectopic Pregnancies (EP)

See article to review table 5.

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