Association between Brain-Derived Neurotrophic Factor (BDNF) Levels in 2nd Trimester Amniotic Fluid and Fetal Development.
Impaired or excessive fetal growth leads to increased rates of perinatal morbidity and mortality . A small for gestational age (SGA) fetus usually refers to a fetus with an estimated fetal weight (EFW) less than the 10th centile, while a severe SGA is a fetus of estimated fetal weight less than the 3rd centile, with the risk of negative pregnancy outcome increasing as we move from small to severe small for gestational age fetuses [2, 3]. Recent data support the additional use of customised birth weight centiles for maternal characteristics, including maternal parity, ethnic origin, height, and weight [4, 5]. Certainly, early antenatal recognition of gestational characteristics allows for closer follow-up and targeted interventions, which are likely to improve outcomes .
Fetal growth restriction (FGR) is not identical with SGA, as FGR denotes a pathological constraint of the genetic growth potential. FGR refers to a fetus whose estimated weight is below the 10th centile for gestational age and who additionally displays signs of chronic malnutrition and hypoxia. The likelihood of growth restriction increases dramatically in severe SGA fetuses. While all structurally normal SGA fetuses are at higher risk of perinatal mortality and morbidity, the majority of adverse outcomes occur among the FGR group . Importantly, however, there is a greater incidence of negative long-term neurodevelopmental, cardiovascular, and endocrinological outcomes among both SGA and FGR fetuses . In any case, a very low EFW (<3rd centile) points to adverse perinatal outcomes regardless of the presence of other indices such as abnormal Doppler findings [9, 10]. Therefore, all otherwise normal fetuses with an EFW below the 3rd centile, as well as those fetuses with an EFW below the 10th centile who manifest signs of fetal compromise, should be considered as FGR, a process mainly caused by chronic placental insufficiency, and need to be closely monitored due to the high risk for an adverse outcome. Moreover, macrosomic or large for gestational age (LGA) fetuses are those with a weight above the 90th centile for gestational age. Though late-gestation fetal growth lowers the risk of perinatal mortality, fetal macrosomia can cause labor complications that may raise the risk of perinatal death [1, 11].
Compromised general fetal development will also affect prenatal central nervous system development, the forming of the most complex structure within the human being. Among these developmental risks is, as mentioned above, chronic placental insufficiency, which can lead to longlasting deficits in neuronal connectivity and function. Both the severity and the timing of these prenatal insults will determine which regions of the brain are affected and how serious will be the damage .
The pathophysiological mechanisms behind impaired or excessive fetal growth have not as yet been entirely elucidated. Despite numerous research efforts, no molecular prognostic marker has to date been identified. We studied a neurotrophic factor which protects fetal nervous system development, differentiation, and metabolism, i.e., brainderived neurotrophic factor (BDNF). BDNF is a member of the neurotrophic growth factor family: it is 52% identical to nerve growth factor (NGF), the neuropeptide that is mainly involved in the regulation of proliferation, growth, maintenance, and survival of a number of target neurons [13, 14]. Among the cells expressing the BDNF molecule are fibroblasts , astrocytes , neurons of various localizations and phenotypes [16-18], megakaryocyte-platelets , Schwann cells , and possibly smooth muscle cells . Two distinct receptors of BDNF have been identified, lowaffinity 75kDa LNGFR (low-affinity nerve growth factor receptor) and high-affinity 145 kDa Tr[kappa]B (tropomyosin receptor kinase-B) . These receptors, after binding BDNF, have important roles to play, namely, implication in growth, differentiation and survival, reverse transportation in neurons, induction of Schwann cell migration, synaptogenesis, and lymphopoiesis [20, 23-26]. To date, while human adult, neonatal, and animal fetal studies involving measurements of BDNF and correlation of these with several aspects of neural growth and function have been carried out, there has been no comparable human fetal research.
The purpose of this study is the detection and quantification of BDNF in the amniotic fluid of 2nd trimester pregnancies. Furthermore, we aim to draw attention to potential correlations between BDNF levels in amniotic fluid and impaired fetal growth as a means of gaining greater insight into the mechanisms underlying fetal growth restriction and macrosomia, which have been linked to maternal, fetal, and neonatal adverse outcomes. It is thus hoped that the present study may reveal a possible prognostic role of this factor as measured in the 2nd trimester and in pregnancy outcome as revealed in the 3rd trimester.
2. Materials and Methods
Amniotic fluid samples were collected from women who had undergone amniocentesis early in the 2nd trimester of gestation (15-22 weeks) based on various indications, such as advanced maternal age, increased nuchal translucency, previous history of birth defects, or detection of an anomaly in the ultrasound examination of the first or 2nd trimester. Immediately after amniocentesis, the amniotic fluid samples were centrifuged and stored in polypropylene tubes at -80[degrees]C. Excluded from the study were twin pregnancies and pregnancies with fetuses of abnormal karyotype or severe congenital malformations. All pregnancies were followed up until delivery. Fetal growth patterns and birth weights were recorded and subsequently divided into three groups: SGA (small for gestational age), AGA (appropriate for gestational age), and LGA (large for gestational age). A gestation-related weight computer program was used to allocate the centile of each neonate at delivery . Our study sample was composed of 31 SGA fetuses and 18 LGA fetuses matched for gestational age, sex, maternal height, and weight and compared with 31 AGA fetuses composing the control group. The corresponding amniotic fluid samples were then withdrawn from our amniotic fluid sample bank, and BDNF was measured in order to compare its levels between normal full-term pregnancies (control group) and the groups of embryos with residual and enhanced growth.
Amniotic fluid BDNF levels were measured using the Quantikine Human BDNF Immunoassay (R&D Systems, Minneapolis, MN, USA) according to the manufacturer's instructions. This Elisa kit is used for cell culture supernates, tissue lysates, serum, EDTA plasma, platelet-poor EDTA plasma, heparin plasma, platelet-poor heparin plasma, urine, and human milk, so it was the most appropriate kit to be used for amniotic fluid. Even more, this ELISA kit has been used effectively for serum BDNF quantification and, given the early 2nd trimester amniotic fluid resemblance in composition with serum, it can be also used for amniotic fluid samples . As the BDNF concentrations in the amniotic fluid were found significantly higher than those of serum, serial dilutions of samples were performed to demonstrate that the Elisa kit used was valid to quantify our BDNF amniotic fluid levels (linear detection). Samples required at least a 20-fold dilution into Calibrator Diluent RD6P prior to the assay. The suggested 20-fold dilution is 10 /l of sample + 190 /l of Calibrator Diluent RD6P. The intra-assay coefficient of variation ranged from 2.4-3.2% and the interassay coefficient of variation ranged from 4.3-7.0%, respectively, while the minimum detectable dose (MDD) of total BDNF ranged from 0.372-1.35 pg/ml.
The results were statistically evaluated by means of the SPSS statistical package using parametric and nonparametric methods, depending on indications. The Kruskal-Wallis test was used for comparison of BDNF concentrations between the three groups. Mean and standard deviations for quantitative variables are displayed in the results. We also applied linear models to examine the difference in BDNF concentrations between different degrees of growth impairment and the control group. In accordance with our study design, confounding factors, including maternal age, body mass index, duration of pregnancy, fetal sex, smoking, and multiparity, were taken into account. Lastly, the distribution of sample values was evaluated by regression analysis (KolmogorovSmirnov test). We set the level of significance at a p value of less than 0.05.
Informed consent was taken from all women who participated in the study. Furthermore, the study was approved by the Ethical Committee for Research of Aretaieio University Hospital, Athens, Greece.
Eighty (80) amniotic fluid samples were measured in total. The descriptive characteristics of the mothers and fetuses are depicted in Table 1. No statistically significant differences were observed as regards maternal weight, maternal height, maternal parity, and duration of gestation among the three groups. However, maternal age, birth weight, and offspring gender were statistically different between groups. The reason for the latter findings may lie in the fact that many SGA fetuses are FGR fetuses and their birth weight is also lower, while LGA fetuses have higher than average weight. Importantly, maternal age is a well-known factor affecting fetal growth, with advanced maternal age being a risk factor for intrauterine growth restriction.
Table 2 and Figure 1 summarize the BDNF assay results showing the mean values of BDNF in the three studied groups, SGA, LGA, and control group. Notably, higher BDNF levels were detected in the amniotic fluid of both SGA and LGA fetuses as compared to normal fetuses (mean values of 36,300 pg/ml and 35,700 pg/ml vs 32,700 pg/ml for SGA and LGA fetuses vs normal fetuses, respectively).
Figure 2 shows that the more severe the growth restriction, the more elevated are amniotic BDNF levels. Normally growing fetuses demonstrate a different pattern compared to growth-restricted fetuses, while fetuses with lower biometry demonstrate lower BDNF levels and those with higher biometry demonstrate higher BDNF levels (Figure 2). This tendency also applies to the fetal macrosomia group, which similarly demonstrates elevated amniotic BDNF levels (Figure 2).
In Table 3, comparison of the distribution of BDNF levels by fetal size is presented. BDNF levels are increased further in women with severe and very severe SGA fetuses. Compared with AGA fetuses, very severe SGA fetuses (below the 3rd centile) display significantly higher BDNF levels. Compared with AGA fetuses, SGA fetuses below the 5th centile, and even the whole group of SGA fetuses (below the 10th centile), demonstrate higher BDNF. Among the group of LGA fetuses demonstrating increased levels of BDNF compared with AGA fetuses, there was no statistical significance.
Although neurotrophins may originate from several origins, like maternal, placental, or fetal compartments, there is evidence that BDNF in second trimester amniotic fluid is mainly of fetal origin . Consequently, second trimester amniotic fluid evaluation reliably reflects the fetal condition and its central nervous system underneath chemo-biological mechanisms in cases of impaired endometrial growth or macrosomia. Research findings further suggest that circulating amniotic fluid neurotrophins can affect fetal neurodevelopment during pregnancy .
To date, while BDNF measurements have been carried out in neonates and adult humans, as well as in animal fetal studies, correlating these with several aspects of neural growth and function, there has been no corresponding human fetal research regarding associations with fetal growth and adaptation to a hostile intrauterine environment. Furthermore, there is also a lack of data concerning the role of neurotrophic factors in macrosomia. Our aim was therefore to measure the amniotic fluid levels of the neurotrophic factor BDNF and to investigate their association with fetal growth.
BDNF and its Tr[kappa]B receptor are widely expressed in both the developing and the adult mammalian brain, with BDNF/TrkB-stimulated intracellular signaling being critical for neuronal activity as well as for neuronal plasticity, protection, metabolism, and survival . Also crucially, BDNF-positive neurons participate in the early development of the frontal lobe of the human fetal cerebrum. During the fourth month of gestation, at which stage our amniocentesis was performed, BDNF-positive neurons grow larger in size and BDNF-positive expression is enhanced . It has further been proposed that maternal BDNF, by reaching the fetal brain via the utero-placental barrier, possibly thereby supports the development of the fetal central nervous system .
Fetal growth restriction (FGR) describes the condition in which a fetus is unable to reach its genetically predetermined growth potential. This may be due to anatomical or functional diseases in the fetal-placental unit, whereby the fetus adapts its circulation to redistribute oxygen, fetal blood flow, and nutrient supply to the vital organs, i.e., the myocardium, brain, and adrenal glands, this phenomenon known as the brain-sparing effect. When this condition persists, it brings about FGR. Given that the brain-sparing effect sometimes occurs in full-term FGR infants, circulating neurotrophin levels should be similar between late nonsevere FGR infants and AGA infants. Previous studies have in fact demonstrated that both groups display similar levels of circulating BDNF, a finding possibly attributable to the activation of the brainsparing effect . Nevertheless, there is still uncertainty as regards the triggering of this response in early or very severe FGR fetuses and macrosomic fetuses.
The neurotrophin family apart from BDNF and NGF is composed of two more structurally related molecules: neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4). Because they exert neuroprotection, neurotrophins play a crucial role in pre- and postnatal brain development. The BDNF neuroprotective effect involves a number of pathophysiologic aspects that include apoptosis, inflammation, intracellular metabolism, and regeneration procedures. In particular, there is strong evidence showing the beneficial impact of BDNF on the survival of neurons via the antiapoptotic effect. The means by which BDNF reduces neuron apoptosis is by enhancing the expression of the Bcl-2 antiapoptosis protein while limiting intracellular calcium overload .
Growth-restricted fetuses may exhibit fetal compromise, with hypoxia being the main underlying pathophysiological mechanism. It has been demonstrated in vitro that in the setting of hypoxia-induced inflammation, BDNF stimulates microglial proliferation and phagocytic activity while elevating the number of phagocytotic microglia and activated microglia, which themselves secrete BDNF . BDNF can suppress TNF-[alpha] and its mRNA expression, this exacerbating ischemia-induced injury, while it increases IL-10 and its mRNA expression, which play an anti-inflammatory neuroprotective role . The putative mechanism behind damage to the developing brain is a neuroinflammatory response in the fetal central nervous system resulting from fetal infection and/or systemic inflammation . What is more, BDNF participates in the parallel activation of anti-inflammatory mechanisms, which are thought to provide negative feedback loops as well as to induce neuroprotective effects and possibly also repair mechanisms in the developing brain .
Glucose depletion and ischemia, by bringing about primary energy failure, trigger a cascade of biochemical events, leading to cell dysfunction. Meanwhile, a resultant reperfusion injury often impairs brain metabolism aggravating the damage caused by oxidative stress, with the main mediator of oxidative stress damage being nitric oxide (NO) [40, 41]. BDNF resists NO-mediated glutamate metabolic cytotoxicity depending on its concentration , the latter comprising a possible neuroprotective role of BDNF in cases of FGR fetuses who present an activated brain-sparing effect, as well as macrosomic fetuses, especially in cases of maternal diabetes. As neurogenesis involves cell proliferation, migration, and differentiation, the augmentation of BDNF around the injured region is critical in facilitating regeneration among central and peripheral neurons [43, 44]. As proinflammatory cytokines, such as TNF-[alpha], IL-1, IL-6, and IL-11, cause serious damage to the capillary endothelium and the alveolar epithelium , BDNF may also protect the fetal respiratory system.
Both in vitro and in vivo animal studies have revealed BDNF to be involved in embryo implantation, placental development, and fetal growth through its stimulation of blastocyst outgrowth [46, 47] and trophoblast cell growth and survival , as well as being necessary for further placental development . Studies on human FGR placentas have shown that expressions of both BDNF and its TrkB receptor mRNA are upregulated .
According to our findings, it seems that an adaptive mechanism accelerates fetal brain development and maturation, a process that is induced by growth restriction chronic hypoxia, this mechanism, expressed by increased BDNF levels, becoming even more enhanced as the growth restriction gets more critical. Interestingly, the above findings are in accord with neonatal studies demonstrating that SGA infants have significantly higher BDNF levels than AGA infants .
Severely growth-restricted fetuses display a pattern of several growth factor disturbances, including PLGF deficiency [52, 53]. Moreover, severely low concentrations of PLGF have been associated with impaired angiogenesis, placentation, and placental development, resulting in complications, notably fetal growth restriction [53, 54]. Meanwhile, there is partial modulation by PLGF of vascular endothelial growth factor (VEGF) activity, the latter factor representing the most potent mediator of angiogenesis . BDNF, a known promoter of endothelial cell survival, induces neoangiogenesis in ischemic tissues, thus complimenting the development of the growth-restricted fetus . BDNF and NGF have, moreover, been implicated in the modulation of angiogenesis .
According to our findings, fetal macrosomia also correlates with elevated BDNF levels, providing a mirror image of BDNF amniotic fluid levels as the fetal growth centile increases, the latter possibly reflecting the advanced fetal and placental mass. Diabetes is a major cause of fetal macrosomia and, by extension, even perinatal morbidity. In addition, intrauterine exposure to a diabetic environment during pregnancy can impact the child long term, since it is associated in the offspring with subclinical vascular inflammation and endothelial dysfunction which are linked to the development of cardiovascular disease later in life . BDNF, as an anti-inflammatory mediator whose levels are increased in macrosomic and diabetic pregnancies, may partially reverse these consequences.
Our study is the first to confirm the presence of the neurotrophic factor BDNF in the amniotic fluid of early midtrimester human pregnancies, with significantly higher BDNF levels being observed in the amniotic fluid of severely growth-restricted fetuses compared to normal fetuses. This concerns a compensatory and adaptive mechanism, induced by growth restriction, which accelerates fetal brain development and maturation. Normally growing and macrosomic fetuses demonstrate a different BDNF pattern from FGR fetuses, leading to a bimodal depiction of BDNF amniotic fluid levels as the fetal growth centile changes.
Through BDNF-stimulated intracellular signaling, BDNF, a neurotrophin widely expressed in the developing fetal brain, plays a vital role in supporting neuronal formation, protection, and metabolism, while it additionally has a major role in placental development and fetal growth. From the clinical perspective, BDNF has been associated with the pathophysiology of a number of pregnancy complications, such as low birth weight and growth restriction. However, it also demonstrates promise as a potential prognostic factor involved in the mechanisms underlying fetal growth restriction and macrosomia, which often give rise to maternal, fetal, and neonatal adverse outcomes. Further studies validating our results and those of previous studies will provide enhanced insight into the processes underlying fetal growth.
The data used to support the findings of this study are available from the corresponding author upon request.
Informed consent was taken from all women who participated in the study. The study was approved by the Ethical Committee for Research of Aretaieio University Hospital, Athens, Greece.
Conflicts of Interest
The authors declare that they have no conflict of interest.
Research and publication of this article was funded by the Postgraduate Studies Program "Research in Female Reproduction" of the National and Kapodistrian University of
Athens Medical School.
 B. Vasak, S. V. Koenen, M. P. H. Koster et al., "Human fetal growth is constrained below optimal for perinatal survival," Ultrasound in Obstetrics & Gynecology, vol. 45, no. 2, pp. 162-167, 2015.
 T. C. Chang, S. C. Robson, R. J. Boys, and J. A. Spencer, "Prediction of the small for gestational age infant: which ultrasonic measurement is best?," Obstetrics and Gynecology, vol. 80, no. 6, pp. 1030-1038, 1992.
 J. Unterscheider, S. Daly, M. P. Geary et al., "Definition and management of fetal growth restriction: a survey of contemporary attitudes," European Journal of Obstetrics, Gynecology, and Reproductive Biology, vol. 174, pp. 41-45, 2014.
 B. Clausson, J. Gardosi, A. Francis, and S. Cnattingius, "Perinatal outcome in SGA births defined by customised versus population-based birthweight standards," BJOG, vol. 108, no. 8, pp. 830-834, 2001.
 F. Figueras, J. Figueras, E. Meler et al., "Customised birthweight standards accurately predict perinatal morbidity," Archives of Disease in Childhood - Fetal and Neonatal Edition, vol. 92, no. 4, pp. F277-F280, 2007.
 J. Gardosi, S. Giddings, S. Clifford, L. Wood, and A. Francis, "Association between reduced stillbirth rates in England and regional uptake of accreditation training in customised fetal growth assessment," BMJ Open, vol. 3, no. 12, article e003942, 2013.
 M. Alberry and P. Soothill, "Management of fetal growth restriction," Archives of Disease in Childhood-Fetal and Neonatal Edition, vol. 92, no. 1, pp. F62-F67, 2007.
 F. Figueras and E. Gratacos, "An integrated approach to fetal growth restriction," Best Practice & Research. Clinical Obstetrics & Gynaecology, vol. 38, pp. 48-58, 2017.
 S. Savchev, F. Figueras, R. Cruz-Martinez, M. Illa, F. Botet, and E. Gratacos, "Estimated weight centile as a predictor of perinatal outcome in small-for-gestational-age pregnancies with normal fetal and maternal Doppler indices," Ultrasound in Obstetrics & Gynecology, vol. 39, no. 3, pp. 299-303, 2012.
 F. Figueras, S. Savchev, S. Triunfo, F. Crovetto, and E. Gratacos, "An integrated model with classification criteria to predict small-for-gestational-age fetuses at risk of adverse perinatal outcome," Ultrasound in Obstetrics & Gynecology, vol. 45, no. 3, pp. 279-285, 2015.
 N. Vrachnis, D. Botsis, and Z. Iliodromiti, "The fetus that is small for gestational age," Annals of the New York Academy of Sciences, vol. 1092, no. 1, pp. 304-309, 2006.
 S. Rees and R. Harding, "Brain development during fetal life: influences of the intra-uterine environment," Neuroscience Letters, vol. 361, no. 1-3, pp. 111-114, 2004.
 E. J. Huang and L. F. Reichardt, "Neurotrophins: roles in neuronal development and function," Annual Review of Neuroscience, vol. 24, no. 1, pp. 677-736, 2001.
 M. Barbacid, "Neurotrophic factors and their receptors," Current Opinion in Cell Biology, vol. 7, no. 2, pp. 148-155, 1995.
 M. Cartwright, A. M. Mikheev, and G. Heinrich, "Expression of neurotrophin genes in human fibroblasts: differential regulation of the brain-derived neurotrophic factor gene," International Journal of Developmental Neuroscience, vol. 12, no. 8, pp. 685-693, 1994.
 G. Moretto, R. Y. Xu, D. G. Walker, and S. U. Kim, "Co-expression of mRNA for neurotrophic factors in human neurons and glial cells in culture," Journal of Neuropathology and Experimental Neurology, vol. 53, no. 1, pp. 78-85, 1994.
 I. Barakat-Walter, "Brain-derived neurotrophic factor-like immunoreactivity is localized mainly in small sensory neurons of rat dorsal root ganglia," Journal of Neuroscience Methods, vol. 68, no. 2, pp. 281-288, 1996.
 C. Wetmore, Y. H. Cao, R. F. Pettersson, and L. Olson, "Brain-derived neurotrophic factor: subcellular compartmentalization and interneuronal transfer as visualized with anti-peptide antibodies," Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 21, pp. 9843-9847, 1991.
 H. Yamamoto and M. E. Gurney, "Human platelets contain brain-derived neurotrophic factor," The Journal of Neuroscience, vol. 10, no. 11, pp. 3469-3478, 1990.
 O. Griesbeck, A. S. Parsadanian, M. Sendtner, and H. Thoenen, "Expression of neurotrophins in skeletal muscle: quantitative comparison and significance for motoneuron survival and maintenance of function," Journal of Neuroscience Research, vol. 42, no. 1, pp. 21-33, 1995.
 I. A. Scarisbrick, E. G. Jones, and P. J. Isackson, "Coexpression of mRNAs for NGF, BDNF, and NT-3 in the cardiovascular system of the pre- and postnatal rat," The Journal of Neuroscience, vol. 13, no. 3, pp. 875-893, 1993.
 F. F. Eide, D. H. Lowenstein, and L. F. Reichardt, "Neurotrophins and their receptors-current concepts and implications for neurologic disease," Experimental Neurology, vol. 121, no. 2, pp. 200-214, 1993.
 L. A. Greene and D. R. Kaplan, "Early events in neurotrophin signalling via Trk and p75 receptors," Current Opinion in Neurobiology, vol. 5, no. 5, pp. 579-587, 1995.
 B. D. Carter, C. Kaltschmidt, B. Kaltschmidt et al., "Selective activation of NF-kappa B by nerve growth factor through the neurotrophin receptor p75," Science, vol. 272, no. 5261, pp. 542-545, 1996.
 M. Barbacid, "The Trk family of neurotrophin receptors," Journal of Neurobiology, vol. 25, no. 11, pp. 1386-1403, 1994.
 M. Maroder, D. Bellavia, D. Meco et al., "Expression of trKB neurotrophin receptor during T cell development. Role of brain derived neurotrophic factor in immature thymocyte survival," Journal of Immunology, vol. 157, no. 7, pp. 2864-2872, 1996.
 J. Gardosi and A. Francis, "Customized centile calculator-GROW-Centile v5.15," Gestation Network, 2009, http://www.gestation.net.
 R. J. Benzie, T. A. Doran, J. L. Harkins, V. M. Jones Owen, and C. J. Porter, "Composition of the amniotic fluid and maternal serum in pregnancy," American Journal of Obstetrics and Gynecology, vol. 119, no. 6, pp. 798-810, 1974.
 M. Deuschle, F. Hendlmeier, S. Witt et al., "Cortisol, cortisone, and BDNF in amniotic fluid in the second trimester of pregnancy: effect of early life and current maternal stress and socioeconomic status," Development and Psychopathology, vol. 30, no. 3, pp. 971-980, 2018.
 Y. Jang, E.-K. Kim, W.-S. Shim, K.-M. Song, and S. M. Kim, "Amniotic fluid exerts a neurotrophic influence on fetal neurodevelopment via the ERK/GSK-3 pathway," Biological Research, vol. 48, no. 1, p. 44, 2015.
 T. Numakawa, S. Suzuki, E. Kumamaru, N. Adachi, M. Richards, and H. Kunugi, "BDNF function and intracellular signaling in neurons," Histology and Histopathology, vol. 25, no. 2, pp. 237-258, 2010.
 L. R. Zheng, X. Q. Zhu, X. M. Huang, Q. Gu, and D. H. Xie, "Morphological study on early development of brain derived neurophic factor-positive neurons in the frontal lobe of human fetus," Zhongguo Yi Xue Ke Xue Yuan Xue Bao, vol. 35, no. 3, pp. 260-264, 2013.
 I. Kodomari, E. Wada, S. Nakamura, and K. Wada, "Maternal supply of BDNF to mouse fetal brain through the placenta," Neurochemistry International, vol. 54, no. 2, pp. 95-98, 2009.
 A. Malamitsi-Puchner, K. E. Nikolaou, and K. P. Puchner, "Intrauterine growth restriction, brain-sparing effect, and neurotrophins," Annals of the New York Academy of Sciences, vol. 1092, no. 1, pp. 293-296, 2006.
 Z. Liu, D. Ma, G. Feng, Y. Ma, and H. Hu, "Recombinant AAV-mediated expression of human BDNF protects neurons against cell apoptosis in Abeta-induced neuronal damage model," Journal of Huazhong University of Science and Technology. Medical Sciences, vol. 27, no. 3, pp. 233-236, 2007.
 J. Zhang, C. Geula, C. Lu, H. Koziel, L. M. Hatcher, and F. J. Roisen, "Neurotrophins regulate proliferation and survival of two microglial cell lines in vitro," Experimental Neurology, vol. 183, no. 2, pp. 469-481, 2003.
 Y. Jiang, N. Wei, T. Lu, J. Zhu, G. Xu, and X. Liu, "Intranasal brain-derived neurotrophic factor protects brain from ischemic insult via modulating local inflammation in rats," Neuroscience, vol. 172, pp. 398-405, 2011.
 N. Vrachnis, N. Vitoratos, Z. Iliodromiti, S. Sifakis, E. Deligeoroglou, and G. Creatsas, "Intrauterine inflammation and preterm delivery," Annals of the New York Academy of Sciences, vol. 1205, no. 1, pp. 118-122, 2010.
 S. Malaeb and O. Dammann, "Fetal inflammatory response and brain injury in the preterm newborn," Journal of Child Neurology, vol. 24, no. 9, pp. 1119-1126, 2009.
 Z. Iliodromiti, A. Anastasiadis, M. Varras et al., "Monocyte function in the fetus and the preterm neonate: immaturity combined with functional impairment," Mediators of Inflammation, vol. 2013, Article ID 753752, 5 pages, 2013.
 Z. Iliodromiti, N. Antonakopoulos, S. Sifakis et al., "Endocrine, paracrine, and autocrine placental mediators in labor," Hormones, vol. 11, no. 4, pp. 397-409, 2012.
 T. Kume, H. Kouchiyama, S. Kaneko et al., Brain Research, vol. 756, no. 1-2, pp. 200-204, 1997.
 N. Kuczewski, C. Porcher, V. Lessmann, I. Medina, and J. L. Gaiarsa, "Activity-dependent dendritic release of BDNF and biological consequences," Molecular Neurobiology, vol. 39, no. 1, pp. 37-49, 2009.
 J. M. Zhu, Y. Y. Zhao, S. D. Chen, W. H. Zhang, L. Lou, and X. Jin, "Functional recovery after transplantation of neural stem cells modified by brain-derived neurotrophic factor in rats with cerebral ischaemia," The Journal of International Medical Research, vol. 39, no. 2, pp. 488-498, 2011.
 Z. Iliodromiti, D. Zygouris, S. Sifakis et al., "Acute lung injury in preterm fetuses and neonates: mechanisms and molecular pathways," The Journal of Maternal-Fetal & Neonatal Medicine, vol. 26, no. 17, pp. 1696-1704, 2013.
 K. Kawamura, N. Kawamura, J. Fukuda, J. Kumagai, A. J. W. Hsueh, and T. Tanaka, "Regulation of preimplantation embryo development by brain-derived neurotrophic factor," Developmental Biology, vol. 311, no. 1, pp. 147-158, 2007.
 K. Kawamura, N. Kawamura, W. Sato, J. Fukuda, J. Kumagai, and T. Tanaka, "Brain-derived neurotrophic factor promotes implantation and subsequent placental development by stimulating trophoblast cell growth and survival," Endocrinology, vol. 150, no. 8, pp. 3774-3782, 2009.
 L. M. Christian, A. M. Mitchell, S. L. Gillespie, and M. Palettas, "Serum brain-derived neurotrophic factor (BDNF) across pregnancy and postpartum: associations with race, depressive symptoms, and low birth weight," Psychoneuroendocrinology, vol. 74, pp. 69-76, 2016.
 M. Dhobale, S. Mehendale, H. Pisal, V. D'Souza, and S. Joshi, "Association of brain-derived neurotrophic factor and tyrosine kinase B receptor in pregnancy," Neuroscience, vol. 216, pp. 31-37, 2012.
 S. Mayeur, M. Silhol, E. Moitrot et al., "Placental BDNF/TrkB signaling system is modulated by fetal growth disturbances in rat and human," Placenta, vol. 31, no. 9, pp. 785-791, 2010.
 C. F. Wang and L. Y. Ye, "Relationship between brain-derived neurotrophic factor and birth weight in neonates," Zhongguo Dang Dai ErKeZa Zhi, vol. 10, no. 1, pp. 70-72, 2008.
 E. Kalampokas, N. Vrachnis, E. Samoli et al., "Association of adiponectin and placental growth factor in amniotic fluid with second trimester fetal growth," In Vivo, vol. 26, no. 2, pp. 327-333, 2012.
 V. Gourvas, E. Dalpa, A. Konstantinidou, N. Vrachnis, D. A. Spandidos, and S. Sifakis, "Angiogenic factors in placentas from pregnancies complicated by fetal growth restriction (review)," Molecular Medicine Reports, vol. 6, no. 1, pp. 23-27, 2012.
 N. Vrachnis, E. Kalampokas, S. Sifakis et al., "Placental growth factor (PlGF): a key to optimizing fetal growth," The Journal of Maternal-Fetal & Neonatal Medicine, vol. 26, no. 10, pp. 995-1002, 2013.
 P. Kermani and B. Hempstead, "Brain-derived neurotrophic factor: a newly described mediator of angiogenesis," Trends in Cardiovascular Medicine, vol. 17, no. 4, pp. 140-143, 2007.
 M. Dhobale, "Neurotrophins: role in adverse pregnancy outcome," International Journal of Developmental Neuroscience, vol. 37, pp. 8-14, 2014.
 N. Vrachnis, N. Antonakopoulos, Z. Iliodromiti et al., "Impact of maternal diabetes on epigenetic modifications leading to diseases in the offspring," Experimental Diabetes Research, vol. 2012, Article ID 538474, 6 pages, 2012.
Nikolaos Antonakopoulos [ID], (1) Zoe Iliodromiti [ID], (1) George Mastorakos, (1) Christos Iavazzo, (2) Georgios Valsamakis [ID], (3) Nikolaos Salakos, (1) Aris Papageorghiou, (4,5) Alexandra Margeli, (6) Sophia Kalantaridou, (1) George Creatsas, (1) Efthymios Deligeoroglou, (1) and Nikolaos Vrachnis (1,4)
(1) Second Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens Medical School, Aretaieio Hospital, Athens, Greece
(2) Gynecological Oncology Department, Metaxa Cancer Hospital, Piraeus, Greece
(3) Department of Endocrinology and Metabolic Disorders, University of Thessaly Medical School, Larissa University Hospital, Larissa, Greece
(4) St George's University of London Medical School and St George's University Hospitals NHS Foundation Trust, London, UK
(5) Nuffield Department of Obstetrics and Gynecology, University of Oxford, Oxford, UK
(6) Department of Clinical Biochemistry, "Aghia Sophia" Children's Hospital, Athens, Greece
Correspondence should be addressed to Nikolaos Antonakopoulos; email@example.com
Received 24 May 2018; Revised 10 October 2018; Accepted 30 October 2018; Published 5 December 2018
Academic Editor: Elena Dozio
Caption: Figure 1: BDNF mean values (pg/ml) and 95% confidence intervals: comparison between groups (1 = SGA, 2 = AGA, 3 = LGA).
Caption: Figure 2: Regression analysis line graph of variables, BDNF (pg/ml) and fetal growth centile: a bimodal depiction of BDNF amniotic fluid levels is shown.
Table 1: Comparative characteristics between groups SGA, LGA, and Control (mean values [+ or -] SD). Variable SGA group N =31 LGA group N =18 Maternal age 37 [+ or -] 3.4 33.5 [+ or -] 5 Maternal weight 69.3 [+ or -] 14.7 59.9 [+ or -] 7.9 Maternal height 166.8 [+ or -] 5 164.7 [+ or -] 7.1 Maternal parity 0.9 [+ or -] 0.9 0.7 [+ or -] 0.7 Fetal sex Mostly XX Mostly XY Birth week 35.5 [+ or -] 9.7 37.8 [+ or -] 1.1 Birth weight 2363.9 [+ or -] 746.3 3870.6 [+ or -] 335.2 (in grams) Variable Control group N = 31 P value Maternal age 34.5 [+ or -] 3.4 0.01 Maternal weight 65.1 [+ or -] 11.1 0.15 Maternal height 167 [+ or -] 5.6 0.60 Maternal parity 0.7 [+ or -] 1 0.24 Fetal sex Mostly XY 0.02 Birth week 38.5 [+ or -] 0.8 0.11 Birth weight 3332.3 [+ or -] 285.1 0.01 (in grams) Table 2: Amniotic fluid BDNF mean values in the three studied groups: SGA, LGA, and Control: both SGA and macrosomic fetuses are characterized by notably higher amniotic fluid levels of BDNF compared to normal-growth fetuses. Group N BDNF (mean value [+ or -] SD) P value SGA 31 36,300 [+ or -] 9000 pg/ml 0.09 LGA 18 35,700 [+ or -] 11,200 pg/ml 0.22 Control 31 32,700 [+ or -] 5700 pg/ml Table 3: Distribution of BDNF (pg/ml) by fetal size group, including the extremes of distribution (divided into three subgroups for each 0th-10th and 90th-100th centile): significantly higher BDNF levels are observed in the amniotic fluid of severely growth-restricted fetuses (below 3rd centile). Fetus N of cases Mean P value AGA 31 32,700 SGA < 10th centile 30 36,300 0.09 SGA < 5th centile 18 36,900 0.09 SGA < 3rd centile 10 40,800 0.01 LGA > 90th centile 18 35,700 0.22 LGA > 95th centile 5 34,600 0.65 LGA > 97th centile 2 35,700 0.53
|Printer friendly Cite/link Email Feedback|
|Title Annotation:||Research Article|
|Author:||Antonakopoulos, Nikolaos; Iliodromiti, Zoe; Mastorakos, George; Iavazzo, Christos; Valsamakis, Georg|
|Publication:||Mediators of Inflammation|
|Date:||Jan 1, 2018|
|Previous Article:||The Role of Immunosenescence in Neurodegenerative Diseases.|
|Next Article:||The Increase of Circulating PD-1- and PD-L1-Expressing Lymphocytes in Endometriosis: Correlation with Clinical and Laboratory Parameters.|