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Serum Biomarkers of Tubal Ectopic Pregnancy: Current Candidates and Future Possibilities

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Serum Biomarkers of Tubal Ectopic Pregnancy: Current Candidates and Future Possibilities REPRODUCTIONREVIEW Serum biomarkers of tubal ectopic pregnancy: current candidates and future possibilities Joanna Cartwright, W Colin Duncan, Hilary O D Critchley and Andrew W Horne Division of Reproductive and Developmental Sciences, Simpson Centre for Reproductive Health, The University of Edinburgh, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SB, UK Correspondence should be addressed to A W Horne; Email: [email protected] Abstract Ectopic pregnancy remains a considerable cause of maternal morbidity and mortality worldwide. Currently, it is diagnosed using a combination of transvaginal ultrasound and serial serum b-human chorionic gonadotrophin levels. Diagnosis is often delayed and these tests are time-consuming and costly, both psychologically to the patient and financially to health services. The development of a biomarker that can differentiate a tubal ectopic from an intrauterine implantation is therefore important. In the pre-genomic era, a one-by-one scientific approach has revealed over 20 candidate biomarkers that could be used as a test to diagnose ectopic pregnancy although at present their clinical utility is very limited. These biomarkers cluster into themes: markers of abnormal embryo/trophoblast growth, markers of abnormal corpus luteum function, markers of a growing pregnancy in the Fallopian tube, markers of inflammation and peritoneal irritation, and uterine markers of normal implantation. It is likely that this thematic approach will facilitate the identification of newer biomarkers using microarray technology and inform the development of investigative paradigms using multiple markers at the time of presentation. Reproduction (2009) 138 9–22 Introduction serum b-hCG measurements. However, it is difficult to distinguish between an ectopic pregnancy, spon- Tubal ectopic pregnancy is an important cause of taneous abortion and early ongoing intrauterine maternal morbidity that can be fatal if left undiagnosed pregnancy using a single b-hCG measurement therefore due to the risk of potential tubal rupture and haemor- repeated b-hCG measurements are taken (Gracia & rhage. Every year in the UK there are w11 000 cases of Barnhart 2001). Generally, a doubling of serum b-hCG tubal ectopic pregnancy (11.5 per 1000 pregnancies) concentrations over 48 h is classed as a normal rise and four maternal deaths due to ruptured tubal ectopic and is therefore suggestive of viable intrauterine pregnancies (0.4 per 1000 tubal ectopic pregnancies; pregnancy (Lenton et al. 1982). If the rise is abnormal Tay et al. 2000, Lewis 2007). The incidence of tubal or b-hCG concentrations are static, then an ectopic ectopic pregnancy is increasing not only in the UK but pregnancevent more likely. A tubal ectopic pregnancy worldwide most likely due to a rising incidence of pelvic can then be inferred by repeated b-hCG measurements or inflammatory disease caused by Chlamydia trachomatis confirmed by endometrial curettage or a more invasive infection and the increased use of assisted reproductive laparoscopy. techniques (Farquhar 2005, Walker 2007). Difficulties diagnosing tubal ectopic pregnancy Current approaches for diagnosing tubal ectopic A tubal ectopic pregnancy can be difficult to diagnose at pregnancy an early stage as nearly a third of all cases do not exhibit In general, the majority of patients presenting with pain clinical signs and 9% have no symptoms prior to rupture or bleeding in early pregnancy have an ultrasound scan (Tay et al. 2000). In addition, when a woman presents to ascertain the viability of the pregnancy and if possible with a suspected pregnancy, in up to half the cases the the location of the gestational sac (Gracia & Barnhart diagnosis is not made on the basis of the initial 2001). If the ultrasound proves inconclusive, a serum consultation, scan and b-hCG estimation despite the b-human chorionic gonadotrophin (b-hCG) level is improvement in the resolution of ultrasonography ascertained. The diagnosis of an ectopic pregnancy is (Duncan et al. 1995, Robson & O’Shea 1996, Munro then based on the combined sonographic findings and et al.2008). The requirement for serial b-hCG q 2009 Society for Reproduction and Fertility DOI: 10.1530/REP-09-0060 ISSN 1470–1626 (paper) 1741–7899 (online) Online version via www.reproduction-online.org Downloaded from Bioscientifica.com at 10/02/2021 02:54:04PM via free access 10 J Cartwright and others assessment involves multiple clinic attendances and than just the cohort of women in whom the diagnosis there are ongoing difficulties in separating failing early is difficult and large prospective studies are rare. intrauterine pregnancies from tubal ectopic pregnancies. However, in the pre-genomic era, a logical approach The diagnosis of tubal ectopic pregnancy is therefore to biomarker identification has resulted in several often time-consuming and costly, both psychologically candidate biomarkers of varying potential. These to the patient and financially to health services markers follow several themes (Fig. 1 and Tables 1–5) (CJ Wedderburn, P Warner, WC Duncan, B Graham & and it is likely that these themes can inform novel AW Horne, unpublished observations). Consequently, a biomarker identification and serum diagnostic strategies serum biomarker (Atkinson et al. 2001)oftubal in the post-genomic era. implantation, which could accurately identify an ectopic pregnancy at first presentation, would be a major clinical Markers of abnormal embryo/trophoblast growth advance (Cabar et al. 2008). A serum biomarker has been defined by the Biomarkers Definitions Working The first theme and indeed the primary current Group as ‘a characteristic that is objectively measured investigative strategy for the diagnosis of tubal ectopic and evaluated as an indicator of normal biological pregnancy are focused on molecules secreted from the processes, pathogenic processes, or pharmacologic conceptus (Table 1). It is likely that pregnancy implanted responses to a therapeutic intervention’ (Atkinson et al. in the tubal environment will have abnormal growth 2001). As there are no suitable animal models of tubal kinetics that can be reflected in disordered measurable ectopic pregnancy, research into putative biomarkers is trophoblast function. This is characterised by the carried out in women. In most studies, serum concen- abnormal dynamics of serum b-hCG concentrations in trations of a putative biomarker are retrospectively ectopic pregnancy. measured in cohorts of women with a diagnosis of tubal ectopic pregnancy, ongoing intrauterine pregnancy Human chorionic gonadotrophin and spontaneous abortion. This paradigm introduces major problems with interpretation of biomarker utility Serum measurement of the b-subunit of hCG is currently as the numbers are small, there are gestational the only biomarker that is routinely used clinically to aid differences, the samples are often collected from more the diagnosis of ectopic pregnancy. It has been studied Figure 1 Serum biomarker themes. Reproduction (2009) 138 9–22 www.reproduction-online.org Downloaded from Bioscientifica.com at 10/02/2021 02:54:04PM via free access Serum biomarkers of tubal ectopic pregnancy 11 Table 1 Markers of abnormal embryo/trophoblast growth. Biomarker Description Utility as biomarker References b-Human chorionic Hormone produced by Serial measurements used Seppala & Purhonen (1987), Riss et al. (1989), gonadotrophin trophoblast that maintains the currently in clinical practice Garcia et al. (1990), Guillaume et al. (1990), (b-hCG) corpus luteum Witt et al. (1990), Mantzavinos et al. (1991), Grosskinsky et al. (1993), Kuscu et al. (1993), Cacciatore et al. (1994), Daily et al. (1994), Korhonen et al. (1996), O’Leary et al. (1996), Mol et al. (1997), Marill et al. (1999), Condous et al. (2004), Mueller et al. (2004) and Seeber et al. (2006) Pregnancy-associated Protease produced by placental Not useful as single predictive Seppala & Purhonen (1987), Sjoberg (1987), plasma protein trophoblast marker of ectopic pregnancy Mueller et al. (2004) and Daponte et al. (2005) A (PAPPA) Pregnancy-specific Glycoprotein produced by Lower in ectopic pregnancy. Ho & Jones (1980), Seppala & Purhonen (1987), b-1-glycoprotein placental trophoblast Potential biomarker. Need Tornehave et al. (1987), Witt et al. (1990), (Schwangerschaft more studies Mantzavinos et al. (1991) and Mueller et al. protein, SP-1) (2004) Human placental Placental hormone that Not useful as single predictive Kuscu et al. (1993), Mueller et al. (2004) and lactogen (HPL) increases marker of ectopic pregnancy Daponte et al. (2005) insulin production Activin A Glycoprotein of TGFB1 Lower in ectopic. 100% Florio et al. (2007) and Kirk et al. (2008) superfamily that is produced sensitivity and 100% by the pregnant decidua and specificity. Discounted in most ovary recent study due to much lower sensitivity and specificity. Need more studies extensively as a marker of ectopic pregnancy over the should be at least 66% and that this would not be the last 30 years (Rasor & Braunstein 1977). Much of the case in ectopic pregnancy. However, 15% of normal early research suggested that serum b-hCG levels were intrauterine pregnancies showed a suboptimal increase reduced in ectopic pregnancy (Lundstrom et al. 1979, and a strict cut-off for the diagnosis of ectopic Milwidsky et al. 1980). However, the true value of pregnancy would lead to unnecessary laparoscopies. b-hCG measurement in ectopic pregnancy is based on Subsequent studies have suggested that the minimum two crucial concepts.
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