Vaginal ultrasound obsolete? Fibroblast growth factor 21 as a new diagnostic tool in missed abortion

Spontaneous miscarriage is the most common pregnancy failure. Over two thirds of fertilized oocytes fail to implant in a preclinical stage, whereas in the remaining 40%, every fourth pregnancy ends in a miscarriage. Missed abortion (MA) is characterized as the undetected decease of the embryo without clinical symptoms and occurs in 10%–15% of pregnancies. Contributing factors include genetic, anatomical, endocrine, and immunologic alterations. Transvaginal sonography serves as a routine diagnostic tool in daily gynecological practice and has significantly improved diagnosis and management of early pregnancy failure. So far, miscarriage is diagnosed via an algorithm using ultrasound examination: an empty gestational sac with a mean diameter of ≥25 mm, or a crown-rump length of ≥7 mm with no visible heartbeat is considered as a miscarriage (1Jurkovic D. Overton C. Bender-Atik R. Diagnosis and management of first trimester miscarriage.BMJ. 2013; 346: f3676Crossref PubMed Scopus (108) Google Scholar). Still, in some women, ultrasound findings are insufficient and (repeated) measurements of biomarkers, such as human chorionic gonadotropin or progesterone, are necessary to confirm the diagnosis. However, the long-known and widely used markers of decreasing human chorionic gonadotropin and low serum progesterone concentrations only identify women with symptomatic pregnancy failures at the time of vaginal bleeding, and biomarkers that identify women at risk of a miscarriage before the symptom onset are lacking. In this month’s issue of Fertility and Sterility, Yang et al. (2Yang Y, Wu J, Wang X, Yao J, Lao KS, Qiao Y, et al. Circulating fibroblast growth factor 21 as a potential biomarker for missed abortion in humans. Fertil Steril. 2021;116:1040–9.Google Scholar) reported the results of a cross-sectional study on serum hormone profiles of fibroblast growth factor 21 (FGF21) and fatty acid-binding protein-4 (FABP4) in two independent cohorts investigating patients with MA. Both markers were previously shown to play a role in glucose metabolism of the placenta and in gestational hypertension. The discovery cohort comprised 78 patients with MA that were compared to 86 controls (matched by body mass index and age) in which levels of FGF21 and FABP4 significantly differed in patients with MA compared to the controls. To further validate their results, the authors recruited an external cohort of MA patients and healthy pregnant women undergoing dilation and curettage for nonmedical reasons. Among these patients, they confirmed that FGF21 and FABP4 levels were significantly increased in MA patients independently of other covariates for MA like maternal or gestational age, history of pregnancy, or miscarriage. Furthermore, compared to FABP4, a single measurement of serum FGF21 levels distinguished women with MA from gravida of healthy pregnancies with an area under the curve of 0.81. The authors studied FGF21 expression in the placenta but did not identify the placenta as a major contributor to FGF21 levels. They did, however, show lower FGF receptor and other vascular growth factor levels in the placentas of MA patients. Furthermore, a histopathological examination showed altered syncytial sprouts in MA patients. This indicates a role of the FGF21 pathway, not only in placental endocrine metabolism, but also in vascular development of the placenta. Therefore, the study not only provided insights in potential biomarkers for MA, but also in the complex regulation of placentation in general. For example, an altered vascularization pattern was also shown in recurrent miscarriage patients with altered natural killer cell levels, indicating a possible link to immunomodulatory therapeutic strategies in MA patients. But how should these findings be introduced into daily practice and which patients are benefited? Is vaginal ultrasound no longer needed to identify patients with MA, or should sonography only be performed in patients with elevated FGF21-levels? Previous studies tried to identify markers for MA. For example, a large, prospective study successfully identified angiogenic factors, such as soluble Fms-like tyrosine kinase 1 and placental growth factor, as stratification tools for viable vs. nonviable pregnancies and concluded that “clinical implications remain to be elucidated” (3Andersen L.B. Dechend R. Karumanchi S.A. Nielsen J. Joergensen J.S. Jensen T.K. et al.Early pregnancy angiogenic markers and spontaneous abortion: an Odense Child Cohort study.Am J Obstet Gynecol. 2016; 215: 594.e1-594.e11Abstract Full Text Full Text PDF Scopus (10) Google Scholar). Furthermore, as researchers and clinicians also see early pregnancy failures as a mechanism for aborting nonviable fetuses (which is supported by the large number of fetuses with abnormal karyotypes or morphological malformations), whether spontaneous miscarriages should even be prevented it remains a topic of debate. Therefore, the results of the present study need to be confirmed in a larger, multiethnic population that is controlled for both normal and disturbed glucose metabolism and provides multiple measurements of FGF21 and FABP4 during gestation. The study is, nonetheless, pointing the finger on the large, but understudied, group of MA patients that would benefit from early diagnostic and preventive measures. In a recent Lancet Series on sporadic and recurrent miscarriage, Coomarasamy et al. (4Coomarasamy A. Gallos I.D. Papadopoulou A. Dhillon-Smith R.K. Al-Memar M. Brewin J. et al.Sporadic miscarriage: evidence to provide effective care.Lancet. 2021; 397: 1668-1674Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar) identified out several key points in their search for evidence to provide effective care in sporadic miscarriage patients. Regarding preventive measures, they could only identify the use of progesterone in cases of women with early pregnancy bleeding or previous miscarriages as a beneficial therapy. However, in these patients, a 15% increase in live births underlines the achievable improvements of a successful treatment in case of patient-selection based on clinical or biochemical markers! Additionally, early recognition of fetuses with abnormal karyotypes by screening for cell-free fetal deoxyribonucleic acid in women at increased risk of spontaneous miscarriage may further identify women that benefit from a therapeutic approach. Considering the imminent health burden by (recurrent) miscarriages, including a higher risk for cardiovascular disorders, such as atherosclerosis, cerebral infarction, or heart failure, and possibly even more severe mental disorders (5Westergaard D. Nielsen A.P. Mortensen L.H. Nielsen H.S. Brunak S. Phenome-wide analysis of short- and long-run disease incidence following recurrent pregnancy loss using data from a 39-year period.J Am Heart Assoc. 2020; 9e015069Crossref PubMed Scopus (11) Google Scholar), more effort is needed to prevent this condition. Perhaps, FGF21 will help us to do that! Circulating fibroblast growth factor 21 as a potential biomarker for missed abortion in humansFertility and SterilityVol. 116Issue 4PreviewTo investigate whether serum levels of fibroblast growth factor 21 (FGF21) and fatty acid-binding protein-4 (FABP4) are associated with missed abortion (MA) in humans. Full-Text PDF