STUDY QUESTION Does administration of recombinant human granulocyte colony stimulating factor (rhG-CSF) in the first trimester improve pregnancy outcomes, among women with a history of unexplained recurrent pregnancy loss? SUMMARY ANSWER rhG-CSF administered in the first trimester of pregnancy did not improve outcomes among women with a history of unexplained recurrent pregnancy loss. WHAT IS KNOWN ALREADY The only previous randomized controlled study of granulocyte colony stimulating factor in recurrent miscarriage in 68 women with unexplained primary recurrent miscarriage found a statistically significant reduction in miscarriage and improvement in live birth rates. A further four observational studies where G-CSF was used in a recurrent miscarriage population were identified in the literature, two of which confirmed statistically significant increase in clinical pregnancy and live birth rates. STUDY DESIGN, SIZE, DURATION A randomized, double-blind, placebo controlled clinical trial involving 150 women with a history of unexplained recurrent pregnancy loss was conducted at 21 sites with established recurrent miscarriage clinics in the United Kingdom between 23 June 2014 and 05 June 2016. The study was coordinated by University of Birmingham, UK. PARTICIPANTS/MATERIALS, SETTING, METHODS One hundred and fifty women with a history of unexplained recurrent pregnancy loss: 76 were randomized to rhG-CSF and 74 to placebo. Daily subcutaneous injections of recombinant human granulocyte - colony stimulating factor 130 g or identical appearing placebo from as early as three to five weeks of gestation for a maximum of 9 weeks. The trial used central randomization with allocation concealment. The primary outcome was clinical pregnancy at 20 weeks of gestation, as demonstrated by an ultrasound scan. Secondary outcomes included miscarriages, livebirth, adverse events, stillbirth, neonatal birth weight, changes in clinical laboratory variables following study drug exposure, major congenital anomalies, preterm births and incidence of anti-drug antibody formation. Analysis was by intention to treat. MAIN RESULTS AND THE ROLE OF CHANCE A total of 340 participants were screened for eligibility of which 150 women were randomized. 76 women (median age, 32[IQR, 29-34] years; mean BMI, 26.3[SD, 4.2]) and 74 women (median age, 31[IQR, 26-33] years; mean BMI, 25.8[SD, 4.2]) were randomized to placebo. All women were followed-up to primary outcome, and beyond to live birth. The clinical pregnancy rate at 20 weeks, as well as the live birth rate, was 59.2% (45/76) in the rhG-CSF group, and 64.9% (48/74) in the placebo group, giving a relative risk of 0.9 (95% CI: 0.7-1.2; P = 0.48). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Adverse events (AEs) occurred in 52 (68.4%) participants in rhG-CSF group and 43 (58.1%) participants in the placebo group. Neonatal congenital anomalies were observed in 1/46 (2.1%) of babies in the rhG-CSF group versus 1/49 (2.0%) in the placebo group (RR of 0.9; 95% CI: 0.1-13.4; P = 0.93). LIMITATIONS, REASONS FOR CAUTION This trial was conducted in women diagnosed with unexplained recurrent pregnancy loss and therefore no screening tests (commercially available) were performed for immune dysfunction related pregnancy failure/s. WIDER IMPLICATIONS OF THE FINDINGS To our knowledge, this is the first multicentre study and largest randomized clinical trial to investigate the efficacy and safety of granulocyte human colony stimulating factor in women with recurrent miscarriages. Unlike the only available single center RCT, our trial showed no significant increase in clinical pregnancy or live births with the use of rhG-CSF in the first trimester of pregnancy. STUDY FUNDING/COMPETING INTEREST(S) This study was sponsored and supported by Nora Therapeutics, Inc., 530 Lytton Avenue, 2nd Floor, Palo Alto, CA 94301, USA. Darryl Carter was the co-founder and VP of research, Nora Therapeutics, Inc. and held shares in the company. He holds a patent for the use of recombinant human granulocyte colony stimulating factor to reduce unexplained recurrent pregnancy loss. Mark Joing, Paul Kwon and Jeff Tong were or are employees of Nora Therapeutics, Inc. No other potential conflict of interest relevant to this article was reported. TRIAL REGISTRATION NUMBER EUDRACT No: 2014-000084-40; ClinicalTrials.gov Identifier: NCT02156063 TRIAL REGISTRATION DATE 31 Mar 2014 DATE OF FIRST PATIENT'S ENROLMENT 23 Jun 2014

As new research reveals, granulocyte colony-stimulating factor (G-CSF) plays an effective role in pregnancy success, considering that it not only affects the embryo implantation and ovarian function but also it promotes endometrial thickening and improves the pathophysiology of endometriosis, which all fundamentally lead to reducing pregnancy loss. In this review, we focus on the role of G-CSF in human reproduction. We summarized its role in ovulation, luteinized unruptured follicle syndrome, poor responders, improving repeated in vitro fertilization failure, endometrial receptivity and treatment of thin endometrium, and recurrent spontaneous abortion.

Granulocyte colony-stimulating factor (G-CSF) administration increased ovarian preantral follicles and anti-Müllerian hormone (AMH) in animal models with diminished ovarian reserve. We investigated whether G-CSF priming before treatment with assisted reproductive technology (ART) improved embryo development and pregnancy rate while increasing serum AMH in patients with poor ovarian reserve.

We investigated whether the protection from graft-versus-host disease (GVHD) afforded by donor treatment with granulocyte colony-stimulating factor (G-CSF) could be enhanced by dose escalation. Donor treatment with human G-CSF prevented GVHD in the B6 --> B6D2F1 murine model in a dose-dependent fashion, and murine G-CSF provided equivalent protection from GVHD at 10-fold lower doses. Donor pretreatment with a single dose of pegylated G-CSF (peg-G-CSF) prevented GVHD to a significantly greater extent than standard G-CSF (survival, 75% versus 11%, P <.001). Donor T cells from peg-G-CSF-treated donors failed to proliferate to alloantigen and inhibited the responses of control T cells in an interleukin 10 (IL-10)-dependent fashion in vitro. T cells from peg-G-CSF-treated IL-10(-/-) donors induced lethal GVHD; T cells from peg-G-CSF-treated wild-type (wt) donors promoted long-term survival. Whereas T cells from peg-G-CSF wt donors were able to regulate GVHD induced by T cells from control-treated donors, T cells from G-CSF-treated wt donors and peg-G-CSF-treated IL-10(-/-) donors did not prevent mortality. Thus, peg-G-CSF is markedly superior to standard G-CSF for the prevention of GVHD following allogeneic stem cell transplantation (SCT), due to the generation of IL-10-producing regulatory T cells. These data support prospective clinical trials of peg-G-CSF-mobilized allogeneic blood SCT.

Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein of Mr of about 20,000, which stimulates proliferation and differentiation of progenitor cells of neutrophils. Recent clinical application of G-CSF has proven that this hormone is effective in treatment of patients suffering from neutropenia. In the last few years, the biochemical and molecular nature of the G-CSF receptor has been characterized. The G-CSF receptor is a glycoprotein of Mr 100-130,000, and is expressed on the cell surface of various myeloid cells. A homodimer of this polypeptide can bind G-CSF with a high affinity, and transduce G-CSF-triggered growth signals into cells. Its extracellular domain contains a sequence of about 200 amino acids which can be found in various cytokine receptors. In addition, it contains an immunoglobulin-like domain and three fibronectin type III domains. The overall structure of the beta-chain (gp130) of the interleukin 6 receptor was found to be very similar to that of the G-CSF receptor.

Three cDNAs for the human granulocyte colony-stimulating factor (G-CSF) receptor were isolated from the cDNA libraries of human U937 leukemia cells and placenta by using a murine G-CSF receptor cDNA as the probe. The human G-CSF receptor containing 813 amino acids had a marked homology (62.5%) with its murine counterpart and consisted of extracellular, transmembrane, and cytoplasmic domains. The WSXWS motif found in members of the newly identified growth factor receptor family was also present in the extracellular domain of the human G-CSF receptor. Expression of the cloned cDNA in monkey COS cells gave rise to a protein that could specifically bind G-CSF with a high affinity (Kd, 550 pM). Two other classes of the human G-CSF receptor were also identified, one of which had a deletion of the transmembrane domain and seemed to encode a secreted, soluble receptor. The third class of the G-CSF receptor contained a 27-amino acid insertion in the cytoplasmic domain and was highly expressed in placenta.

Reproductive immunology applies general immunology principles to specialised targets, reproduction and development. The involvement of colony-stimulating factors (CSFs) in reproduction illustrates this. The CSF family includes CSF-1 or macrophage CSF (M-CSF), CSF-2 or granulocyte macrophage CSF (GM-CSF), and CSF-3 or granulocyte CSF (G-CSF). Each member has a specific localisation and timed expression in the reproductive tract with specific functions involving them in ovulation, embryo implantation, placentation and further embryonic development. They are used in reproductive medicine, either as biomarkers of oocyte quality and competence (follicular G-CSF), or to supplement embryo culture media with human recombinant GM-CSF, or they are used as an innovative therapy by using human recombinant G-CSF for infertile patients. Given fundamental considerations on CSFs and their strong implication in reproduction, this review aimed to detail the current knowledge for each member of the family to improve our understanding of their implication in the maternal-foetal cytokinic dialogue and in possibly preventing reproductive disorders. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Granulocyte colony-stimulating factor (G-CSF) is required for proliferation, differentiation, and survival of cells. It is also a biomarker of human oocyte developmental competence for embryo implantation. In humans, the G-CSF concentration peaks during the ovulatory phase of the ovarian cycle. In this study, the expressions of G-CSF and its receptor were analyzed by polymerase chain reaction in granulosa cells (GCs), CL, cumulus cells (CCs), and oocytes. Cumulus-oocyte complexes were aspirated from antral follicles of 1 to 3 mm (small follicles) and 4 to 6 mm (medium follicles). Cumulus-oocyte complexes from two kinds of follicles were matured in protein-free maturation medium supplemented with various concentrations of G-CSF (0, 10, and 100 ng/mL). By real-time polymerase chain reaction, the expressions of G-CSF and its receptor were detected in GCs, CL, CCs, and oocytes. Interestingly, the G-CSF transcript levels were significantly lower in oocytes than in the other cell types, whereas the G-CSF receptor transcript levels in oocytes were similar to those in GCs. After 44 hours of IVM, no differences in the rate of nuclear maturation were detected; however, the intracellular reactive oxygen species levels in oocytes from both groups of follicles matured with 10 ng/mL of human recombinant G-CSF (hrG-CSF) groups were significantly lower (P < 0.05). After parthenogenetic activation, the cleavage rates were significantly (P < 0.05) higher in 100 ng/mL hrG-CSF-treated small (63.3%) follicles than in 0, 10 ng/mL hrG-CSF-treated small (38.6% and 49.0%, respectively) follicles and 0 ng/mL hrG-CSF-treated medium (52.1%) follicles, and the cleavage rates were significantly (P < 0.05) higher in 10 ng/mL hrG-CSF-treated medium (76.3%) follicles than in all other groups. The blastocyst formation rates were significantly (P < 0.05) higher in 100 ng/mL hrG-CSF-treated small (31.2%) follicles than in 0 and 10 ng/mL hrG-CSF small (10.4% and 15.6%, respectively) follicles, and the 10 ng/mL hrG-CSF medium (45.7%) follicle was significantly (P < 0.05) higher than in all other groups. The total cell number in blastocysts from the 10 ng/mL hrG-CSF medium (106.5) follicles was significantly (P < 0.05) increased compared to 0, 10, 100 ng/mL hrG-CSF small (55.0, 73.7 and 59.5, respectively) follicles and 0, 100 ng/mL hrG-CSF-treated medium (82.5 and 93.5, respectively) follicles. After IVF, the blastocysts stage was significantly (P < 0.05) increased in 10 ng/mL hrG-CSF-treated medium (36.4%) follicles. Fertilization efficiency was significantly high in 100 ng/mL of small (29.1%) and 10 ng/mL of medium (44.0%) follicles. We also examined the Bcl2 and ERK2 transcript levels and found that they were significantly higher in the small and medium follicle treatment groups. In conclusion, these results indicate that hrG-CSF improve the viability of porcine embryos.Copyright © 2015 Elsevier Inc. All rights reserved.

Endometrial receptivity is a prerequisite for the success of assisted reproduction. Patients with a consistently thin endometrium frequently fail to conceive, owing to low endometrial receptivity, and there are currently very few therapeutic options available. Our previous study demonstrated that intrauterine granulocyte-macrophage colony-stimulating factor (GM-CSF) administration resulted in a significant improvement in clinical pregnancy and implantation rates and was an effective means of increasing endometrial thickness on the day of embryo transfer in patients with thin endometrium. In order to explore the underlying process, an animal model with a thin endometrium was constructed, the homeobox A10 gene (HOXA10) was downregulated, and an inhibitor of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway (MAPK/ERK) was employed. Our findings strongly suggest a marked decrease in GM-CSF levels in the thin endometrial rat model, and the suppression of HOXA10 impeded the therapeutic efficacy of GM-CSF in this model. Moreover, we showed that GM-CSF significantly increases endometrial receptivity in the rat model and upregulates HOXA10 via the MAPK/ERK pathway. Our data provide new molecular insights into the mechanisms underlying formation of a thin endometrium and highlight a novel, potential clinical treatment strategy as well as directions for further research.

To evaluate effects of G-CSF on a cancelled ART cycle due to thin endometrium.In a nonrandomized clinical trial from January 2011 to January 2013 in two tertiary university based hospitals fifteen patients undergoing embryo transfer and with the history of cycle cancellation due to thin endometrium were studied. Intrauterine infusion of G-CSF was done on the day of oocyte pick-up or 5 days before embryo transfer. The primary outcome to be measured was an endometrium thickened to at least 6 mm and the secondary outcome was clinical pregnancy rate and consequently take-home baby. All previous cycles were considered as control for each patient.The G-CSF was infused at the day of oocyte retrieval or 5 days before embryo transfer. The endometrial thickness reached from 3.593±0.251 mm to 7.120 ± 0.84 mm. The mean age, gravidity, parity, and FSH were 35.13± 9.531 years, 3, 1 and 32.78 ± 31.10 mIU/ml, respectively. The clinical pregnancy rate was 20%, and there was one missed abortion, a mother death at 34 weeks, and a preterm labor at 30 weeks due to PROM.G-CSF may increase endometrial thickness in the small group of patients who had no choice except cycle cancellation or surrogacy.

The aim of the study was to assess the granulocyte-colony stimulating factor (G-CSF) effect on unresponsive thin (<7 mm) endometrium in women undergoing frozen-thawed embryo transfer at the blastocyst stage. A total of 62 women with thin unresponsive endometrium were included in the study, of which, 29 received a G-CSF infusion and 33 who opted out of the study served as controls. Patients in both groups had similar endometrial thickness at the time of the initial evaluation: 6.50 mm (5.50-6.80) in the G-CSF and 6.40 mm (5.50-7.0) in the control group. However, after the infusion endometrial thickness increased significantly in the G-CSF group in comparison with the controls (p=0.01), (Δ) 0.5 (0.02-1.2) (p=0.005). In the G-CSF group endometrium expanded to 7.90 mm (6.58-8.70) while in the control group to 6.90 mm (6.0-7.75). Five women in each group conceived. The clinical pregnancy rate was 5/29 (17.24%) in the G-CSF treated group and 5/33 (15.15%) in the control group (p>0.05). The live birth rate was 2/29 (6.89%) in the G-CSF group and 2/33 (6.06%) in the control group (p>0.05). We concluded that G-CSF infusion leads to an improvement in endometrium thickness but not to any improvement in the clinical pregnancy and live birth rates. Until more data is available G-CSF treatment should be considered to be of limited value in increasing pregnancy rate.G-CSF: granulocyte colony-stimulating factor; M-CSF: macrophagecolony-stimulating factor; GM-CSF: granulocyte-macrophage colony-stimulating factor; FET: frozen embryo transfer; IVF: in vitro fertilization.

This study was conducted to assess the efficacy of subcutaneous granulocyte colony-stimulating factor (G-CSF) for treating thin endometrium.Data from 88 infertile women with thin endometrium (<7 mm) aged 23 to 40 years were evaluated retrospectively over a period of 1 year. In group 1, subcutaneous infusion of G-CSF (300 μg/mL) was administered to 44 women along with other supplemental treatments. If the lining did not exceed 7 mm within 72 hours, a second infusion was administered. In group 2, which also had 44 women, only estradiol valerate and sildenafil were administered, while subcutaneous G-CSF infusion was not. Embryo transfers were performed once the lining exceeded 7.5 mm. The efficacy of G-CSF was evaluated by assessing the thickness of the endometrium before embryo transfer, pregnancy rates, and clinical pregnancy rates.There were no differences between the groups regarding demographic variables, egg reserves, sperm parameters, the number of embryos transferred, and embryo quality. The pregnancy rate was significantly higher in group 1 (60%, 24 of 40 cases) than in group 2 (31%, 9 of 29 cases) (p<0.001). The clinical pregnancy rate was also significantly higher in group 1 (55%) than in group 2 (24%) (p<0.001).Subcutaneous G-CSF infusion improved the thickness of the endometrium when it was thin. To the best of our knowledge, this is the first documented study to clearly demonstrate the benefits of subcutaneous G-CSF infusion for treating thin endometrium.

We aimed to evaluate the effectiveness of granulocyte colony-stimulating factor (G-CSF) administration for infertile women with thin endometrium in frozen embryo transfer program. Among 59 infertile patients with thin endometrium (≤7 mm), 34 patients received uterine infusion of recombinant human G-CSF (100 μg/0.6 mL) on the day of ovulation or administration of progesterone or human chorionic gonadotropin, with 40 cycles defined as G-CSF group and 49 previous cycles as self-controlled group, and 25 patients refused, with 80 cycles defined as the control group. Higher proportion of induced cycles and lower proportion of natural cycles were observed in the G-CSF group, when compared to the self-controlled group or control group (P <.05). The cycle cancellation rate was, in descending order, 69.39% in self-controlled group, 48.75% in control group, and 17.50% in G-CSF group, with significant difference (P <.05). The implantation rate and clinical pregnancy rate per embryo transfer were similar in all the groups (P >.05). Our study fails to demonstrate that G-CSF has the potential to improve embryo implantation and clinical pregnancy rate of the infertile women with thin endometrium.

We often see patients with a thin endometrium in ART cycles, in spite of standard and adjuvant treatments. Improving endometrial growth in patients with a thin endometrium is very difficult. Without adequate endometrial thickness these patients, likely, would not have reached embryo transfer.We planned this study to investigate the efficacy of intrauterine granulocyte colony-stimulating factor (G-CSF) perfusion in improving endometrium, and possibly pregnancy rates in frozen-thawed embryo transfer cycles.This is a non-randomized intervention clinical trial. Among 68 infertile patients with thin endometrium (-7 mm) at the 12(th)-13(th) cycle day, 34 patients received G-CSF. G-CSF (300 microgram/1mL) to improve endometrial thickness was direct administered by slow intrauterine infusion using IUI catheter. If the endometrium had not reached at least a 7-mm within 48-72 h, a second infusion was given. Endometrial thickness was assessed by serial vaginal ultrasound at the most expanded area of the endometrial stripe.The cycle was cancelled in the patients with thin endometrium (endometrial thickness below 7mm) until 19(th) cycle day ultimately The cycle cancelation rate owing to thin endometrium was similar in G-CSF group (15.20%), followed by (15.20%) in the control group (p=1.00). The endometrial growth was not different within 2 groups, an improvement was shown between controlled and G-CSF cotreated groups, with chemical (39.30% vs. 14.30%) and clinical pregnancy rates (32.10% vs. 12.00%) although were not significant.Our study fails to demonstrate that G-CSF has the potential to improve endometrial thickness but has the potential to improve chemical and clinical pregnancy rate of the infertile women with thin endometrium in frozen-thawed embryo transfer cycle.

This study aimed to evaluate the effectiveness of granulocyte colony-stimulating factor (G-CSF) for infertility and recurrent spontaneous abortion.

Recurrent implantation failure (RIF) is the absence of implantation after three consecutive In Vitro Fertilization (IVF) cycles with transferring at least four good quality embryos in a minimum of three fresh or frozen cycles in a woman under 40 years. The definition and management of RIF is under constant scrutiny.To investigate the effects of Granulocyte colony stimulating factor (G-CSF) on RIF, pregnancy rate, abortion rate and implantation rates.A double blind placebo controlled randomized trial was conducted at two tertiary university based hospitals. One hundred patients with the history of RIF from December 2011 until January 2014 were recruited in the study. G-CSF 300µg/1ml was administered at the day of oocyte puncture or day of progesterone administration of FET cycle. Forty patients were recruited at G-CSF group, 40 in saline and 20 in placebo group.The mean age for whole study group was 35.3±4.2 yrs (G-CSF 35.5±4.32, saline 35.3±3.98, placebo 35.4±4.01, respectively). Seventeen patients had a positive pregnancy test after embryo transfer [10 (25%) in G-CSF; 5 (12.5%) in saline; and 2 (10%) in placebo group]. The mean of abortion rates was 17.6% (3), two of them in G-CSF, one in saline group. The implantation rate was 12.3% in G-CSF, 6.1% in saline and 4.7% in placebo group.G-CSF may increase chemical pregnancy and implantation rate in patients with recurrent implantation failure but clinical pregnancy rate and abortion rate was unaffected.

This study investigates the effects of intrauterine G-CSF on endometrial thickness, clinical pregnancy rate and live birth rate in a recurrent implantation failure (RIF) group with normal endometrium. This study was designed as a prospective randomized controlled trial with the involvement of 157 RIF group pati; ents. The RIF group was formed on the basis of the RIF criteria: "The failure to achieve a clinical pregnancy after the transfer of at least four good-quality embryos in a minimum of three fresh or frozen cycles to a woman under the age of 40 years. The study sample included 82 patients in the G-CSF group who received G-CSF once a day on hCG. The procedure was performed by administering 30 mIU of Leucostim®(Filgrastim [G-CSF] 30 mIU/mL; DEM Medical, Dong-A; South Korea) through slow infusion into the endometrial cavity using a soft embryo transfer catheter. Normal saline of 1 mL was infused into the endometrial cavity in the same way in 75 patients in the control group. The standard ICSI procedure was used for all patients, and fresh cycle embryos were transferred on the third or fifth day. No statistically significant difference was identified in clinical pregnancy rates, miscarriage rates and live birth rates between the G-CSF group and the control group (p = 0.112, p = 0.171, p = 0.644, respectively), and no difference was observed between the two groups regarding endometrial thickness (p = 0.965). The intervention of administration G-CSF into the uterine cavity in RIF patients with normal endometrium, did not alter the endometrial thickness, clinical pregnancy rates, or live birth rates.

In 1980, Espey proposed a famous hypothesis that mammalian ovulation is comparable to an inflammatory reaction and many researches have proved the validity of his hypothesis in the last three decades. For example, interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)- alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF) and other inflammatory cytokines presence was proven in the preovulatory follicle. Since granulocyte is the major leukocyte and it plays a very important role during inflammation, the importance of granulocyte and its related cytokine, granulocyte colony-stimulating factor (G-CSF) in the mechanism of human ovulation is easily predictable. G-CSF is one of the hemopoietic cytokines and it has strong positive effects on granulocytes. G-CSF increases the number of granulocytes and it improves the function of granulocytes. In this review, the participation of leukocytes in the ovulation mechanism is demonstrated first. Second, the participation of G-CSF is shown in comparison with the above mentioned cytokines. Finally, since G-CSF has been used for more than 20 years as a medicine without severe side effects in the field of oncology, the clinical application of G-CSF for the treatment of an ovulation disorder, luteinized unruptured follicle (LUF), will be discussed.

Splenic rupture is an infrequent and underdiagnosed side effect of granylocyte colony-stimulating factor (G-CSF). We report the case of a 54-year-old woman with brain and bone metastasis in a lung adenocarcinoma who was admitted for faintness 28 days after a G-CSF injection. Abdominal CT scan confirmed the diagnosis of splenic rupture. A conservative treatment was chosen using a peritoneal cleansing during laparoscopic surgery. Clinicians should be aware of this rare toxicity as it could be severe, but easily reversible using appropriate surgical treatment. Even if prognosis remains poor for patients with lung cancer, invasive procedures could be considered in this rapidly evolving setting, especially in case of reversible adverse event.

Capillary leak syndrome (CLS) is a well-known phenomenon that has been reported commonly in association with septic shock, polytrauma, and pancreatitis in intensive care settings. In the hematologic literature, it has been reported following granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor, tumor necrosis factor, interleukin 2, and interleukin 4 infusions; and autologous and allogenic bone marrow transplantations in both pediatric as well as adult populations. Only a few cases of CLS have been reported in the pediatric population following G-CSF. We report here a case of a 9-year-old female who developed CLS within 60 minutes of receiving the first dose of G-CSF that was successfully treated with immediate symptomatic management.Copyright. Pediatric Pharmacy Association. All rights reserved. For permissions, email: membership@pediatricpharmacy.org.

To report outcomes associated with the administration of granulocyte colony-stimulating factor (G-CSF) to women with chronic neutropenia during pregnancy.We conducted an observational study of women of childbearing potential with congenital, cyclic, idiopathic, or autoimmune neutropenia enrolled in the Severe Chronic Neutropenia International Registry to determine outcomes of pregnancies, without and with chronic G-CSF therapy, 1999-2014. Treatment decisions were made by the patients' personal physicians. A research nurse conducted telephone interviews of all enrolled U.S. women of childbearing potential using a standard questionnaire. Comparisons used Fisher's exact test analysis and Student's t test.One hundred seven women reported 224 pregnancies, 124 without G-CSF therapy and 100 on chronic G-CSF therapy (median dose 1.0 micrograms/kg per day, range 0.02-8.6 micrograms/kg per day). There were no significant differences in adverse events between the groups considering all pregnancies or individual mothers, for example, spontaneous terminations (all pregnancies: no G-CSF in 27/124, G-CSF in 13/100; P=.11, Fisher's exact test), preterm labors (all pregnancies, no G-CSF in 9/124, G-CSF in 2/100, P=.12). A study with at least 300 per group would be needed to detect a difference in these events with 80% statistical power (α=0.05). Four newborns of mothers with idiopathic or autoimmune neutropenia not on G-CSF (4/101) had life-threatening infections, whereas there were no similar events (0/90) in the treated group, but this difference was also not statistically significant (P=.124). Adverse events in the neonates were similar for the two groups.This observational study showed no significant adverse effects of administration of G-CSF to women with severe chronic neutropenia during pregnancy.III.

Gastrointestinal (GI) tract development is influenced by multiple growth factors, some of which are delivered directly to the GI lumen, as they are swallowed constituents of amniotic fluid, colostrum, and milk. Granulocyte colony-stimulating factor (G-CSF), traditionally known as a granulocytopoietic growth factor, is an example of one such factor. However, it is not clear whether the large amounts of G-CSF that are normally swallowed by the fetus and neonate have systemic effects on circulating neutrophils or local effects in the developing intestine. To assess this, we administered either active or heat-denatured (control) recombinant human G-CSF to 5- to 7-d-old C57BL/6 x 129SvJ mice. Pups received either a low dose (3 ng) that was calculated to approximate the amount of G-CSF swallowed in utero from amniotic fluid or an isovolemic high dose 100 times larger (300 ng). Oral dosing was performed daily for either 3 or 7 d, after which pups were killed and measurements were made on the blood and the GI tract. Absolute blood neutrophil counts and immature to total neutrophil ratios did not differ from controls in any of the test groups. However, intestinal villus area, perimeter, length, crypt depth, and proliferating cell nuclear antigen index increased significantly among those that were treated with active G-CSF. Thus, in suckling mice, enterally administered G-CSF had no effect on the concentration of circulating neutrophils but had trophic effects on the intestine. We speculate that the G-CSF present in amniotic fluid, colostrum, and milk acts as a topical intestinal growth factor and has little or no granulocytopoietic action.