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ORIGINAL RESEARCH |
From the 1Department of Obstetrics and Gynaecology, Monash University, Monash Medical Centre, Clayton, Victoria, Australia; and 2Monash IVF, Clayton, Victoria, Australia.
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ABSTRACT |
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METHODS: This was an observational retrospective study of 1,054 women who underwent in vitro fertilization and achieved an ultrasound-confirmed live singleton pregnancy with cardiac activity. The incidence of miscarriage diagnosed at 8–19 weeks +6 days of gestation was estimated in these 3 subgroups according to their hCG concentrations at day 16 after conception: less than the 25th, 25th–75th, and more than the 75th percentiles.
RESULTS: The overall incidence of miscarriage was 11.1% (117/1,054), and the median gestational age at diagnosis was 10 weeks and 4 days. The median (95% confidence interval) day 16 hCG level in the miscarriage group was 182 mIU/mL (157–211), significantly lower than the median level in those who had an ongoing pregnancy (223 mIU/mL [213–233], P < .003). There was an increasing risk of miscarriage associated with decreased hCG levels (8.0% at > 75th percentile; 9.9% at 25th–75th percentiles; 16.7% at < 25th percentile; P = .003).
CONCLUSION: Low hCG levels in very early pregnancy are associated with an increased risk of miscarriage occurring after the clinical recognition of pregnancy. The mechanisms underlying late first-trimester and second-trimester miscarriages may have begun as early as the first week of implantation.
LEVEL OF EVIDENCE: III
It has not been precisely determined how early the pathogenic events that lead to clinical miscarriage might begin. Although it is clear that low levels of hCG around days 12–16 after conception (fourth week of gestation) are associated with preclinical early pregnancy loss,12 the precise relationship between early hCG levels and clinical (later) miscarriage remains uncertain. Previous studies have generally grouped clinical miscarriages with preclinical early pregnancy loss7 and ectopic pregnancies5,6,13,14 as a single outcome and have not separated twins from the analysis. Twins would introduce a significant bias because they are associated with higher early hCG levels,6,13 and rates of clinical miscarriage may be different from those of singletons.15,16
We therefore undertook an observational study to investigate whether low hCG levels at day 16 after conception were associated with an increased risk of clinical miscarriage diagnosed after the 8th week of gestation. Importantly, we only included cases where there was early ultrasound evidence confirming the presence of a viable singleton pregnancy with demonstrable cardiac activity. We hypothesized that a low, but positive, hCG measured during the first week of implantation might reflect lower embryo or implantation quality, placing the pregnancy at increased risk of miscarriage, even after progressing to clinical recognition.
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MATERIALS AND METHODS |
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In Australia, IVF centers are mandated to collect and report clinical outcomes to a national government body, and data collected for this purpose were used to undertake the study. This study was approved by Monash Surgical Private Hospital Ethics Committee, Clayton, Australia.
Baseline data were collected on age, the type of assisted reproductive technology (ART), previous number of deliveries (none versus one or more), the type of infertility, and the number of embryos transferred. For our primary outcome, we estimated the incidence of miscarriage in the 3 subgroups in which day 16 hCG levels were less than the 25th percentile, greater than the 75th percentile, or between the 25th and 75th percentiles. We also obtained information regarding at which period of gestation the miscarriage was diagnosed.
We only included women who had undergone IVF and had a clinically recognized, viable, singleton pregnancy with normal fetal cardiac activity confirmed by ultrasound examination. An early-pregnancy ultrasound examination is routinely performed, usually timed to occur during the sixth week of gestation, in all women who undergo IVF treatment and may be pregnant. We restricted our analysis to pregnancies reaching the eighth week of gestation because we were concerned that including miscarriages occurring at 6–7 weeks of gestation might introduce a bias, whereby a woman who miscarried around this time might or might not be included in our cohort depending on whether she had attended her ultrasound examination. We anticipated that the early-pregnancy ultrasound examination would have been done in almost all cases by the eighth week of gestation. Our final definition of a clinical miscarriage, for the purposes of our study, was a pregnancy loss diagnosed between 8+0 and 19+6 weeks of gestation, while an ongoing pregnancy was one that had progressed beyond 20 weeks. The diagnosis of miscarriage would have either been made clinically or discovered at a routine ultrasound examination, such as the 11- to 13-week scan screening for Down syndrome. We have a dedicated health professional who contacts the patient and/or the treating clinician to obtain accurate outcomes for all IVF pregnancies to comply with national regulations.
Women undergoing IVF cycles were administered the gonadotropin-releasing hormone (GnRH) agonist nafarelin (Synarel; Searle, High Wycombe, UK) for pituitary desensitization, followed by subcutaneous recombinant human follicle stimulating hormone (rhFSH; Gonal-F; Ares-Serono, Geneva, Switzerland). When the dominant follicle or follicles were more than 17 mm in diameter, both nafarelin and rhFSH were discontinued, and before oocyte retrieval, 5,000–10,000 IU of hCG (Profasi; Serono Laboratories, Geneva, Switzerland) was administered. The oocytes were fertilized in vitro and transferred after 2–3 days. Luteal support was provided by administration of 400 mg daily progesterone vaginal suppositories. After a 6- to 7-week ultrasound scan confirming viability, the ordering of remaining scans is left to the discretion of the treating clinician.
Human chorionic gonadotropin levels were measured with an immunometric assay and performed on an automated system (VitrosECi; OrthoDiagnostics, Rochester, NY). The intra- and interassay coefficient of variation was less than 10%, and the sensitivity of the assay was 0.5 mIU/mL. Student t test was used to analyze parametric data and the Mann-Whitney U or Kruskal-Wallis for nonparametric data. Proportions were compared by using the 
2 test.
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RESULTS |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The overall miscarriage rate was 11.1% (n = 117). The median day 16 hCG level in the miscarriage group was 182 (95% confidence interval [CI] 157–211) mIU, significantly lower than the median level for those who had an ongoing pregnancy: 223 (95% CI 213–233) mIU (P < .003, Mann-Whitney U). There was a significant inverse association between risk of clinical miscarriage and day 16 hCG level (8.0% at > 75th percentile; 9.9% at 25–75th percentiles; 16.7% at < 25th percentile; P < .003, 2; Table 2).
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The median (25th–75th percentiles) gestational age at which women were diagnosed with miscarriage was 10+4 (95% CI 9+2–12+0) weeks. The gestational ages at diagnosis were similar, irrespective of day 16 hCG levels (P = .143, Kruskal-Wallis; Table 2) although there appeared to be a trend toward a later diagnosis with higher hCG levels.
Because women in the miscarriage cohort were significantly older, we undertook a post hoc analysis correlating maternal age and day 16 serum hCG levels. In both the miscarriage cohort and ongoing pregnancy groups, a weak but significant positive correlation existed between maternal age and hCG (r2 = 0.068, P = .005; and r2 = 0.0064, P = .002, respectively, Pearson correlation).
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DISCUSSION |
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Although an association between low hCG and an increased risk of preclinical pregnancy losses in IVF pregnancies has been well established,5,6,13,14 the relationship with clinical miscarriage has remained, until now, relatively obscure because prior reports have grouped preclinical loss, clinical pregnancy loss, and ectopic pregnancies as a single outcome.4–7,14 Although Poikkeus et al8 also grouped these outcomes as "nonviable," they did separately report day 12 hCG values among a cohort undergoing a clinical miscarriage and found them to be at half the values of those who had viable pregnancies. While this is in agreement with our findings, extrapolation of their data should be cautious because a comparison between these 2 subgroups was not the focus of their paper. Thus, no statistical comparison of baseline details or hCG results between these 2 subgroups was provided. Frishman et al18 found an increased risk of miscarriage among 130 women who had low hCG levels (
20 mIU/mL) at 4 weeks gestation and singleton intrauterine gestational sacs on ultrasonography. Unlike our study, this small study did not document fetal cardiac activity.
Importantly, the miscarriage rate we observed was 11.1%. This is in agreement with the rates of 10.3% and 12% observed by others after a sixth week of gestation viability scan in a spontaneous19 and IVF singleton cohorts,16 respectively. This suggests that our findings may have broader application beyond an IVF cohort.
We found that those in the miscarriage cohort were still significantly older, but a post hoc analysis demonstrated a positive correlation between age and hCG in both the miscarriage and the ongoing pregnancy cohorts. This would exclude increased maternal age as the cause of low early hCG in the miscarriage cohort.
The main implications of our findings are that a significant proportion of clinical miscarriages have their origins in very early pregnancy. Many of these cases are likely to be a deliberate expulsion of conceptuses containing chromosomal errors, which occur in as many as 55%1 of miscarriages. We can only speculate about what underlying pathology might be reflected in a low day 16 hCG level, but it is likely to indicate poorer implantation. Wilcox et al2 found that the optimum period for an embryo to implant is 8–10 days after conception in a cohort of women with a spontaneous pregnancy and that cases in which the first positive hCG levels were detected after this time incurred a significant increase in the risk of preclinical pregnancy loss. Low day 16 hCG may, therefore, reflect late implantation, where hCG secretion from the trophoblast starts after day 10, with levels remaining low by day 16. It has also been recently shown in that same study population that inadequate hCG doubling times during the first week of implantation were also associated with an increased risk of preclinical loss.20 This might also result in low day 16 hCG in those destined for clinical miscarriage. This would suggest that the etiology may not lie with the timing of implantation but rather with implantation quality.
Previous trials of progesterone therapy to prevent spontaneous miscarriage in the general population21 and the use of hCG22 and immunotherapies23 to prevent recurrent miscarriage have generally not been successful. Therapies tested in these trials usually commenced well after the first week of implantation. If the pathogenic events leading to some cases of late miscarriage are indeed beginning this early, then a partial explanation of why these trials have not shown a benefit is that treatments may have been started too late.
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Footnotes |
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doi:10.1097/01.AOG.0000196505.09016.f3
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REFERENCES |
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2. Wilcox AJ, Baird DD, Weinberg CR. Time of implantation of the conceptus and loss of pregnancy. N Engl J Med 1999;340:1796–9.
3. Wang X, Chen C, Wang L, Chen D, Guang W, French J. Conception, early pregnancy loss, and time to clinical pregnancy: a population-based prospective study. Fertil Steril 2003;79:577–84.[Medline]
4. Legro RS, Paulson RJ, Lobo RA, Sauer MV. Association of early beta-human chorionic gonadotrophin values with pregnancy wastage and multiple implantation in a donor oocyte programme. Hum Reprod 1995;10:3293–6.
5. Glatstein IZ, Hornstein MD, Kahana MJ, Jackson KV, Friedman AJ. The predictive value of discriminatory human chorionic gonadotropin levels in the diagnosis of implantation outcome in in vitro fertilization cycles. Fertil Steril 1995;63:350–6.[Medline]
6. Homan G, Brown S, Moran J, Homan S, Kerin J. Human chorionic gonadotropin as a predictor of outcome in assisted reproductive technology pregnancies. Fertil Steril 2000;73:270–4.[Medline]
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8. Poikkeus P, Hiilesmaa V, Tiitinen A. Serum HCG 12 days after embryo transfer in predicting pregnancy outcome. Hum Reprod 2002;17:1901–5.
9. Wilcox AJ, Weinberg CR, O’Connor, JF, Baird DD, Schlatterer JP, Canfield RE, et al. Incidence of early loss of pregnancy. N Engl J Med 1988;319:189–94.[Abstract]
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16. Tummers P, De Sutter, P, Dhont M. Risk of spontaneous abortion in singleton and twin pregnancies after IVF/ICSI. Hum Reprod 2003;18:1720–3.
17. Norwitz ER, Schust DJ, Fisher SJ. Implantation and the survival of early pregnancy. N Engl J Med 2001;345:1400–8.
18. Frishman GN, Hackett RJ, McGrath M, Metheny WP. Evaluation of the prognosis of in vitro fertilization pregnancies with initially low serum human chorionic gonadotropin levels. Am J Obstet Gynecol 2001;185:392–5.[Medline]
19. Makrydimas G, Sebire NJ, Lolis D, Vlassis N, Nicolaides KH. Fetal loss following ultrasound diagnosis of a live fetus at 6-10 weeks of gestation. Ultrasound Obstet Gynaecol 2003;22:368–72.[Medline]
20. Baird DD, Weinberg CR, McConnaughey DR, Wilcox AJ. Rescue of the corpus luteum in human pregnancy. Biol Reprod 2003;68:448–56.
21. Goldstein P, Berrier J, Rosen S, Sacks HS, Chalmers TC. A meta-analysis of randomized control trials of progestational agents in pregnancy. Br J Obstet Gynaecol 1989;96:265–74.[Medline]
22. Scott JR, Pattison N. Human chorionic gonadotrophin for recurrent miscarriage (Cochrane Review). In: The Cochrane Library, Issue 2, 2000. Oxford: Update Software.
23. Intravenous immunoglobulin in the prevention of recurrent miscarriage. The German RSA/IVIG Group. Br J Obstet Gynaecol 1994;101:1072–7.[Medline]
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
