Recurrent pre-clinical pregnancy loss is unlikely to be a 'cause' of unexplained infertility

Department of Reproductive Medicine and Gynaecology, University Medical Centre Utrecht, F05.126, PO Box 85500, 3508 GA Utrecht, The Netherlands.
Human Reproduction (Impact Factor: 4.57). 07/2011; 26(10):2636-41. DOI: 10.1093/humrep/der217
Source: PubMed


A proportion of women with 'unexplained' infertility may present with subfertility because their pregnancies fail before they are clinically recognized. In order to test whether pre-clinical early pregnancy losses (EPL) occur more frequently in women with unexplained infertility, serial urinary hCG concentrations were measured to compare EPL per cycle rates following spontaneous conception in patients with unexplained infertility versus healthy volunteers.
Sixty patients under 39 years of age with unexplained infertility and 60 healthy controls, who were trying to conceive spontaneously, participated in this study. All participants were asked to collect daily urine samples from cycle day 14 until menstruation for three consecutive cycles or until a positive pregnancy test was obtained. Urinary hCG and creatinine levels were measured by immunoassay. Implantation was detected when urinary hCG levels rose above reference levels constructed from samples obtained from 12 women not attempting to conceive. EPL rates were determined by a linear mixed model using logarithmically transformed hCG/creatinine data.
In the 133 cycles of 60 women with unexplained infertility, just one implantation was detected, which became an ongoing pregnancy. In contrast, in 103 such cycles in 46 control patients, 30 implantations were detected (24 clinical pregnancies, 6 cases of EPL). The odds ratio for EPL/cycle in the unexplained versus control group was 0 (95% confidence interval: 0-0.795, P = 0.026).
Our data do not support the hypothesis that recurrent EPL may present as unexplained infertility. Post-implantation failure is therefore unlikely to contribute significantly to the presentation of subfertility.

9 Reads
  • Source
    • "In contrast to these studies, knockout mice for various isoforms of NOS do not show reduced litter size (Huang et al., 1993, 1995; MacMicking et al., 1995), indicating the importance of multiple pathways and redundancy in the implantation process. Since implantation failure secondary to endometrial factors may be common to unexplained infertility (Koot et al., 2011) and recurrent miscarriage (Li et al., 2002b), the present study sought to determine if aberrant endometrial expression of eNOS could be associated with these two conditions. The common finding of luminal increase in the expression of eNOS protein in both recurrent miscarriage and unexplained infertility patients suggest that luminal eNOS is important in the pathogenesis of these disorders. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Endothelial nitric oxide synthase (eNOS) has diverse roles in the female reproductive system including a role in blastocyst implantation. Aberrant expression of eNOS could therefore be significant in the pathogenesis of disorders of implantation. In this study, eNOS protein and mRNA levels in the endometrium of women with recurrent miscarriages, unexplained infertility and a control group were determined by compartmental quantitative immunohistochemistry and real-time reverse-transcription PCR. eNOS was found to be immunolocalized to all layers of the endometrium and vascular endothelium. eNOS protein was higher in glandular epithelium (P = 0.004) and luminal epithelium (P = 0.002), but not vascular endothelium and stroma, in women with recurrent miscarriage. Similarly, in women with unexplained infertility, eNOS was significantly higher (P < 0.03) in luminal epithelium but not in any other compartments compared with the control group. The levels of mRNA confirmed the protein data, demonstrating higher eNOS mRNA in the endometrium of women with recurrent miscarriage and unexplained infertility compared with controls. In conclusion, increased expression of eNOS in glandular and luminal epithelium of the endometrium in women with recurrent miscarriages and unexplained infertility suggests a detrimental effect of excess nitric oxide in endometrial receptivity and implantation. RBM Online (c) 2012, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
    Reproductive biomedicine online 07/2012; 25(4):408-14. DOI:10.1016/j.rbmo.2012.07.004 · 3.02 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Successful embryo implantation depends on a well-timed maternal-embryonic crosstalk. Human chorionic gonadotropin (hCG) secreted by the embryo is known to play a key role in this process and to trigger a complex signal transduction cascade allowing the apposition, attachment, and invasion of the embryo into the decidualized uterus. Production of hCG was reported to be dependent on blastocyst quality and several articles suggested that intrauterine hCG injection increases pregnancy and implantation rates in IVF patients. However, no study has as yet analysed birth rates as final outcome. Our objective was to determine whether clinical outcome after blastocyst transfer can be improved by intrauterine injection of hCG and whether this is dependent on blastocyst quality. A prospective randomised study was conducted in two settings. In cohort A, hCG application was performed two days before blastocyst transfer. In cohort B, the administration of hCG occurred just prior to embryo transfer on day 5. For both cohorts, patients were randomised to either intrauterine hCG application or to the control group that received culture medium. Clinical outcome was analysed according to blastocyst quality of transferred embryos. The outcome of 182 IVF-cycles (cohort A) and 1004 IVF-cycles (cohort B) was analysed. All patients received a fresh autologous blastocyst transfer on day five. Primary outcomes were pregnancy rates (PR), clinical pregnancy rates (cPR), miscarriage rates (MR), and live birth rates (LBR). No improvement of clinical outcome after intrauterine hCG administration on day 3 (cohort A) or day 5 (cohort B) was found, independently of blastocyst quality transferred. The final outcome in cohort A: LBR after transfer of top blastocysts was 50.0 % with hCG and 53.3 % in the control group. With non-top blastocysts, LBR of 17.1 % (hCG) and 18.2 % (control) were observed (n.s.). In cohort B, LBR with top blastocysts was 53.3 % (hCG) and 48.4 % (control), with non-top blastocysts it came to 28.7 % (hCG) and 35.0 % (control). The differences between the groups were statistically not significant. Furthermore, we investigated a possible benefit of hCG administration in correlation with female age. In both age groups (<38 years and ≥ 38 years) we found similar LBR after treatment with hCG vs. medium. A LBR of 47.1 % vs. 48.7 % was obtained in the younger group and 26.6 % vs. 30.8 % in the older group. In contrast to previous studies indicating a substantial benefit from intrauterine hCG application in cleavage stage embryo transfers, in our study we could not find any evidence for improvement of clinical outcome in blastocyst transfer cycles, neither with top nor with non-top quality morphology.
    Reproductive Biology and Endocrinology 07/2015; 13(1):70. DOI:10.1186/s12958-015-0069-1 · 2.23 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Bleeding from endometriotic implants is now an established cause of acute hemoperitoneum in pregnancy. However, the adverse impact of pelvic endometriosis on uterine function before conception may also interfere with subsequent deep placentation, accounting for the increased risk of obstetrical complications, including preterm birth and antepartum hemorrhage.
    Fertility and sterility 03/2012; 98(1):30-5. DOI:10.1016/j.fertnstert.2012.02.024 · 4.59 Impact Factor
Show more