1 Early Pregnancy and Gynaecology Assessment Unit, Department of Obstetrics and Gynaecology and 2 Department of Biochemistry, King's College Hospital, London, UK
3 To whom correspondence should be addressed at: Early Pregnancy and Gynaecology Assessment Unit, King's College Hospital, Denmark Hill, London SE5 8RX, UK. Email: davor.jurkovic{at}kcl.ac.uk
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Abstract |
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Key words:
expectant management/IGFBP-1/inhibin A/inhibin pro -C RI/miscarriage
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Introduction |
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Over the last decade, several new biochemical markers of the lutealtrophoblastic axis have been described (Irwin and Guidice, 1998; Glennon Phipps et al., 2000
). However, their potential clinical applications have not been studied extensively so far.
The aim of this study was to investigate the potential value of various novel biochemical markers in combination with clinical and ultrasound findings for the prediction of successful expectant management of first trimester miscarriage.
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Materials and methods |
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All women who opted for expectant management had a blood sample taken for serum HCG, progesterone levels and 17-hydroxyprogesterone (17-OHP) (DRG diagnostics, Germany), and the new serum markers inhibin A (Oxford Bio-innovation, Oxford, UK), inhibin pro -C RI (Oxford Bio-Innovation, Oxford, UK) and insulin growth factor-binding protein-1 (IGFBP-1) (Oxy Medix Biochemica Ab, Finland). The serum markers chosen were those that previous studies had been shown to play a role in the dynamics of the corpus lutealplacentaldecidual axis. HCG production is known to relate directly to the amount of trophoblast present (Zegers-Hochschild et al., 1994
). Progesterone has been shown to play a crucial role in pregnancy maintenance (Sitteri et al., 1977
) and 17-OHP is produced by the corpus luteum and has been shown to be lower in non-viable pregnancies (Check et al., 1990). Of the newer serum markers, inhibin A is also known to reflect both the trophoblast amount and the dynamics of the corpus luteum (Muttukrishna et al., 1994
; Lahiri et al., 2003
) and inhibin pro
-C is a product of the corpus luteum (Lockwood et al., 1997
). Irwin and Guidice (1998)
demonstrated that IGFBP-1 was associated with the placentaldecidual interface, with high levels thought to protect the endometrium from invasion.
Women were then followed-up in line with the unit policies for expectant management of miscarriage. They were all asked to attend 7 days later for a urinary pregnancy test. If this was positive or if there was continued bleeding, then a further transvaginal ultrasound was carried out. A complete miscarriage was diagnosed if the pregnancy test had become negative and the bleeding had settled. Follow-up continued until the miscarriage was completed or women opted for surgical removal of retained products because of worsening of clinical symptoms or for practical reasons because of prolonged follow-up. Expectant management was classified as successful if a complete miscarriage occurred without the need for surgical intervention. The study protocol was approved by the Research Ethics Committee for King's College Hospital, London, and all women gave their informed consent.
A database was established and the data recorded included maternal age, date of last menstrual period, the presence or absence of vaginal bleeding (expressed as bleeding score 0 or 1), mean diameter of products of conception (calculated from measurements taken in three orthogonal planes) and the serum levels of progesterone, HCG, 17-OHP, inhibin A, pro -C inhibin and IGFBP-1. As no previous studies existed using these markers, the sample size was calculated on the assumption that the study would detect a difference between the groups of 1 SD. This, therefore, gave a sample size of 45 at the 5% significance level with 90% power.
All statistical analyses were carried out using SPSS version 10 (SPSS Inc., Chicago, IL). The outcomes were dichotomized into successful and failed expectant management categories. Comparison of means of continuous variables was performed using MannWhitney or Student's t-tests depending on data distribution. Proportions were compared using the Yates corrected 2 test. A value of P<0.05 was considered statistically significant.
Data were analysed using decision tree analysis. This tree-based analysis was carried out using SPSS answerTree version 2.1 (SPSS Inc., Chicago, IL). Twelve independent variables were used for construction of the decision tree and these included maternal age, gestational age, diameter of products of conception, serum progesterone level, serum HCG level, serum inhibin A level, serum 17-OHP level, serum pro -C inhibin level, serum IGFBP-1 level, pregnancy type, presence or absence of pain and presence or absence of bleeding. All except the last three were entered as continuous variables.
A decision tree was developed using the Classification and Regression Trees (C&RT) method. The stopping rules for the iterative process were that the tree should have a maximum of five levels, a minimum of five cases were to be present for a split to be calculated and any given split should not generate a group with less than two cases. This allows sequential analysis of variables to predict whether the final management would be expectant or surgical.
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Results |
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Comparison of the initial findings in women with successful and failed expectant management showed significant differences in the size of retained products of conception, serum HCG, progesterone, inhibin A and inhibin pro -C RI (Table I)
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Discussion |
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This study has also shown that some of the novel biochemical markers may be used at the initial visit to identify women in whom miscarriage is likely to be completed spontaneously. Undetectable serum inhibin A was strongly associated with successful expectant management, indicating a low amount of retained functioning trophoblast. Persistent functioning trophoblast is probably the main factor leading to failed expectant management and it would seem that serum inhibin A levels reflect the trophoblastic activity more accurately than HCG. Of those pregnancies where the inhibin was still measurable, high concentrations of IGFBP-1 were associated with successful expectant management. Two hypotheses exist for the action of IGFBP-1 in early placentation. One is that higher concentrations of IGFBP-1 are thought to inhibit binding of the trophoblast to the decidual cells (Irwin and Guidice, 1998). The second is that there is overproduction of IGFBP-1 by the decidua response to defective implantation. In this study, the presence of a raised IGFBP-1 concentration was associated with an increased chance of successful expectant management. This is the first time that raised IGFBP-1 concentrations have been described in association with miscarriage. It suggests that high levels reflect a defect in the attachment of the trophoblast to the decidua, thus resulting in an increased chance of the retained products being expelled spontaneously.
In those women with high IGFBP-1, lower levels of inhibin pro -C RI were associated with an increased success of expectant management. Inhibin pro
-C RI is known to be a product of the corpus luteum and has been shown to drop during termination of pregnancy (Lahiri et al., 2003
). It is not known whether the mechanism responsible for lower levels of inhibin pro
-C RI in successful expectant management reflects a poorly functioning corpus luteum or whether inhibin pro
-C RI levels are low in response to feedback from lower levels of HCG. Previous studies have suggested that pro
-C RI may be responsible for maintaining luteal progesterone output that may or may not be HCG mediated (Webley et al., 1994
).
Using the decision tree analysis for management of miscarriages alone, successful outcome could be predicted in 81% of the population. This compares favourably with the logistic regression model of Nielsen et al. (1996). The use of colour Doppler as advocated by Schwarzler et al. (1999)
predicts successful outcome with a probability of 80% but only in 54% of the population. Recently Wieringa-de Waard et al. (2002)
demonstrated that using initial expectant management of miscarriage can reduce the number of surgical procedures required by 37%. The same group has also demonstrated improved mental health scores in women undergoing expectant management. The major limitation with uptake of expectant management is the inability to predict which women are likely to have spontaneous pregnancy resolution. Decision tree analysis as presented in this study could be used for both patient selection and counselling. However, the efficacy and the cost-effectiveness of the proposed model have to be evaluated in a prospective study before it can be recommended for use in clinical practice.
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References |
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Submitted on November 25, 2004; resubmitted on March 19, 2005; accepted on March 23, 2005.
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