Skip to main content
main-content

15.09.2018 | Review | Ausgabe 5/2018 Open Access

Archives of Gynecology and Obstetrics 5/2018

Therapeutic role of granulocyte colony-stimulating factor (G-CSF) for infertile women under in vitro fertilization and embryo transfer (IVF-ET) treatment: a meta-analysis

Zeitschrift:
Archives of Gynecology and Obstetrics > Ausgabe 5/2018
Autoren:
Ling Zhang, Wei-Hai Xu, Xiao-Hua Fu, Qiong-Xiao Huang, Xiao-Yan Guo, Lin Zhang, Shi-Shi Li, Jing Zhu, Jing Shu
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1007/​s00404-018-4892-4) contains supplementary material, which is available to authorized users.
Joint first authors: Ling Zhang and Wei Hai Xu.

Introduction

Implantation of a competent blastocyst into receptive endometrium is key to build a successful pregnancy [1]. Despite major advancement in reproductive medicine over the last few decades, implantation failure still makes frequent appearance during the process of assisted reproductive technology (ART) [2, 3]. Repeated implantation failure (RIF), generally defined as failure of three in vitro fertilization and embryo transfer (IVF-ET) cycles in which one or two high-grade quality embryos were transferred to the patient in each cycle [4], represents an enormous emotional and financial burden for the patient. Poor endometrial receptivity has been generally considered as a major cause of the failure of embryo implantation, and endometrial thickness as an important component of endometrial receptivity [5]. Several therapies have been proposed for solving the problem in endometrial receptivity, such as extended estrogen administration, treatment with low-dose aspirin, vaginal sildenafil citrate, and treatment with pentoxifylline and tocopherol, and proven successful in some cases. However, many cases still remain resistant to these treatments [5].
Successful embryo implantation requires an intricate biological interaction between the implanting embryo and the host endometrium [6]. A bulk of molecular factors have been implicated in this complex process, including endometrial integrins, extracellular matrix molecules, adhesion molecules, growth factors, and ion channels [1]. Granulocyte colony-stimulating factor (G-CSF) belongs to the family of colony-stimulating factors (CSF) synthesized by multiple cell types (e.g., endothelial cells, fibroblasts, macrophages, lymphocytes) [7, 8], and has been proven to originate from some reproductive tissue cells as well, such as human ovary [9] and endometrium [10]. Particularly, some pieces of evidence have showed that G-CSF or its receptor be located in luteinized granulosa cells, placenta trophoblastic cell and oocytes [1113]. Currently, several physiological roles have been suggested for G-CSF during the process of pregnancy forming, i.e., promoting embryo cleavage and blastocyst formation [13], regulating endometrial expressions crucial for a series of implantation processes including endometrial vascular remodeling, local immune modulation and cellular adhesion pathways [14], and targeting follicle development and ovulation [15].
The therapeutic effect of G-CSF in patients with RIF has been investigated as early as 2000 by Würfel and the colleagues, and the results show that systematic administration of G-CSF is able to enhance the implantation rate dramatically [16]. Since then, bulks of similar studies have been conducted for RIF cases due to poor endometrial thickness or other reasons, but the conclusions are inconsistent. Even in rigorously randomized control trials (RCTs), only about half reach a conclusion that G-CSF can improve the endometrium thickness, implantation rate or clinical pregnancy rate after IVF treatment [1618], while the remains negative [1923]. This inconsistence might be owing to the heterogeneity in administration route or clinical conditions between studies. Indeed, currently published studies were structured into various designs, such as randomized control trials (RCTs), observational studies, self-controlled trials or single arm studies; included subjects of different clinical conditions including RIF, thin endometrium or unselected patients, and did not adapt the same administration route, systematic injection or intrauterine infusion.
Single study may be limited by sample size, research design, administration route, clinical conditions, or patient’s ethnicity and age, and underpowered to achieve a comprehensive and reliable conclusion. Meta-analysis has the benefit to overcome this limitation by increasing the sample size. Therefore, this study was designed to explore the efficacy of G-CSF on infertile patients undergoing IVF-ET treatment with RIF.

Methods and procedures

The review protocol was registered in PROSPERO (CRD42018056662). Randomized controlled trials (RCTs) comparing G-CSF treatment versus the control were included in this meta-analysis. Pseudo-randomized trials were excluded.
We collected the relevant studies by searching the databases of Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase and ISI Web of Science updated in July, 2017, using the keywords: (‘Granulocyte colony stimulating factor’ OR ‘Granulocyte Colony-Stimulating Factor’ OR ‘G-CSF’ OR ‘CSF’) AND (‘Assisted Reproductive Techniques’ OR ‘ART’ OR ‘In Vitro Fertilization’ OR ‘IVF’ OR ‘Intracytoplasmatic Sperm Injection’ OR ‘ICSI’OR ‘embryo transfer’ OR ‘FET’). There were no limitations on the type of the publication. All languages were accepted. We also searched for study protocols and ongoing trials in ClinicalTrials.gov (https://​clinicaltrials.​gov/​). References of retrieved articles were also screened.
Our primary outcome measure was clinical pregnancy rate (CPR) per woman randomly assigned, and the secondary one implantation rate (IR) per embryo transferred. All literatures were reviewed independently by two authors. The flow chart for study selection was shown in Fig. 1. Two authors extracted data independently and in duplicate, and reached on all items including author’s last name, journal and year of publication, country of origin, ethnicity of the patients, definition of RIF or thin endometrium, count of each event in GSF group and the control. The results were compared and disagreements were discussed and resolved with consensus.
Risk of bias in individual study was structured using the Cochrane risk of bias assessment tool to assess: selection (random sequence generation and allocation concealment); performance (blinding of participants and personnel); detection (blinding of outcome assessors); attrition bias (incomplete outcome data); reporting bias (selective outcome reporting) and other potential sources of bias. The trials were classified as being at ‘low’, ‘high’ or ‘unclear’ risk of bias.
The pooled RRs and their 95% confidence interval (CI) were estimated to assess the role of G-CSF treatment on the outcomes of IVF-ET. The pooled RRs were calculated through a Mantel–Haenszel fixed effects model if there was no heterogeneity. Otherwise, a random-effects model was adopted. Subgroup analysis was performed by administration route and clinical indications. Statistical heterogeneity across studies was formally tested using Cochran’s test. The I2 statistic was examined and I2 > 50% was considered significant for the heterogeneity between studies. An influence analysis was conducted to describe how robust the pooled estimator is after removal of individual studies. An individual study was suspected of excessive influence if the point estimate of its omitted analysis lies outside the 95% CI of the combined analysis. Publication bias across studies was assessed using the Egger regression test and Begg’s funnel plot. All analyses were conducted in Stata software (Version 14.0; Stata Corporation, College Station, TX, USA).

Results

Study characteristics

The last electronic search was conducted in July 25, 2017, retrieving a total of 971 records. After screening the titles and abstracts, we removed 894 records including 609 duplicates and 285 ones that did not meet the eligibility criteria. A total of 77 records were further examined for eligibility, and 61 removed for non-RCT design (n = 52) or non-maternal administration route (n = 9). Finally, 16 articles were included into the stage of data extraction, then 4 excluded for duplicating data [2427], 2 for logical error in published data [28, 29] and 1 without data regarding the IVF outcome. Finally, a total of ten studies were included in this meta-analysis [1623, 30, 31].
With these ten articles published between 2000 and 2016, 1036 IVF-ET patients in all were randomized, from a wide range of regions including Europe [16, 18, 21, 31], North America [19] and Asia [17, 20, 22, 23, 30]. Among all studies, one evaluated the role of G-CSF treatment for unselected patients [19], one for the cases with thin endometrium [20], and remaining eight for those with RIF [1618, 2123, 30, 31]. The detailed characteristics of these studies are shown in Table 1.
Table 1
Characteristics of the studies included in the meta-analysis
Author, year
Country
Period of enrolment
Publication type
Sample size
Female age (years) CSF/control
Indications
Diagnostic criteria
Inclusion and exclusion criteria
Aleyasin A, 2016 [25]
Iran
March 2015–January 2016
Origin article
112
33.5 ± 4.2/32.4 ± 5.2
RIF
Transferred embryos fail to implant after three IVF cycles
< 40 years, with normal endometrium thickness, and without sensitivity of GCSF, or any systemic disease, or detection of Asherman’s syndrome, fibroids and/or polyps
Barad DH, 2014 [19]
USA
October 2010–January 2013
Origin article
141
39.79 ± 5.13/39.38 ± 6.03
Unselected
With normal endometrial thickness, and without renal disease, sickle cell disease, or a history of malignancy
Davari-Tanha F, 2016 [23]
Iran
December 2011–January 2014
Origin article
80
35.5 ± 4.32/35.3 ± 3.98
RIF
History of three times implantation failure with at least four good-quality embryos
< 40 years, without uterine, thrombophilic factors, or history of renal disease, sickle cell disease or malignancy or sensitivity of G-CSF
Eftekhar M, 2016 [22]
Iran
October 2014–February 2015
Origin article
90
32.55 ± 4.61/31.75 ± 5.16
RIF
At least two implantation failures
20–40 years, without sickle cell disease, chronic neutropenia, malignancy history, renal failure, congenital fructose intolerance, respiratory infection, endometriosis, or sever male factor
Kim CH, 2011 [30]
South Korea
NR
Meeting abstract
82
NR
RIF
At least three previous failed IVF attempts with good quality embryos
29–40 years, without thrombophilia or anatomic abnormalities of uterine cavity
Obidniak D, 2016, part I [21]
Russia
NR
Meeting abstract
130
NR
RIF
At least two previous failed IVF attempts with good-quality blastocysts
32–40 years, with normal endometrial thickness and availability of vitrified blastocyst, without congenital uterine anomalies or Asherman’s syndrome
Obidniak D, 2016, part II [21]
Russia
NR
Meeting abstract
130
NR
RIF
At least two previous failed IVF attempts with good-quality blastocysts
32–40 years, with normal endometrial thickness and availability of vitrified blastocyst, without congenital uterine anomalies or Asherman’s syndrome
Scarpellini F, 2011 [31]
Italy
NR
Meeting abstract
89
NR
RIF
NR
NR
Scarpellini F, 2012 [18]
Italy
January 2008–December 2010
Meeting abstract
109
NR
RIF
At least three previous failed IVF attempts with at least seven good embryos
< 39 years, absence of systemic diseases
Singh R, 2015 [20]
India
January 2014–December 2014
Meeting abstract
48
< 40
Thin endometrium
NR
< 42 years
Würfel W, 2000 [16]
Germany
NR
Meeting abstract
138
NR
RIF
At least three previous failed IVF attempts with at least five embryos and more than 50% embryos transferred in good quality
< 40 years, undergoing the fourth or fifth IVF or ICSI cycle
Author, year
Drug route/dose
Administration time
Description of the control
Protocol
Embryo age
Previous failure
CSF/control
Embryos transferred
CSF/control
Good embryos transferred (%)
CSF/control
Aleyasin A, 2016 [25]
Subcutaneously
300 μg
1 h before the ET
No therapy
Fresh ET
D3
3/3
2.3 ± 0.6/2.5 ± 0.6
NR
Barad DH, 2014 [19]
Intrauterine infusion
300 µg
The morning of hCG administration
Normal saline
Fresh or frozen ET
D3 or D5
NR
2.41/2.47
45.57/39.29
Davari-Tanha F, 2016 [23]
Intrauterine infusion
300 μg
At the time of oocyte retrieval. In FET cycle, at the day of starting progesterone
Normal saline
Fresh or frozen ET
D3 or D5
3.5 ± 2.1/4.2 ± 1.5
NR
NR
Eftekhar M, 2016 [22]
Intrauterine infusion
300 μg
At the time of oocyte retrieval
Without GSF infusion
Fresh ET
D3
2.57 ± 1.69/3.41 ± 1.54
2.11/2.35
61.4/57.80
Kim CH, 2011 [30]
NR
100 µg × 2
The day of ET and the fourth day after ET
Fresh ET
D3
NR
NR
NR
Obidniak D, 2016, part I [21]
Intrauterine infusion
300 μg
5 days prior to ET, or at the day of ET
No therapy
Frozen ET
Blastocyst
NR
NR
NR
Obidniak D, 2016, part II [21]
Subcutaneously
300 μg
5 days prior to ET, or at the day of ET
No therapy
Frozen ET
Blastocyst
NR
NR
NR
Scarpellini F, 2011 [31]
Subcutaneously
1.5 mg/kg/day
From the day of transfer to the day of hCG test, and if it was positive the treatment was continued for other 40 days
Normal saline
Fresh ET
NR
NR
NR
NR
Scarpellini F, 2012 [18]
Subcutaneously
60 mg/daily
From the day of transfer to the day of hCG test, and if it was positive the treatment was continued for other 40 days
Normal saline
NR
NR
NR
NR
NR
Singh R, 2015 [20]
Intrauterine infusion
300 µg or 300 µg × 2
The morning of hCG administration
Normal saline
Fresh ET
NR
NR
NR
NR
Würfel W, 2000 [16]
Systematically
300 μg
On the day of ET
NR
NR
NR
NR
NR

Meta-analysis

Ten studies all described the role of studied administration on CPR after ART. Figure 2a showed the forest plots RRs on CPR, and the pooled RR value was 1.89 (95% CI 1.53–2.33, P = 0.00), indicating that G-CSF treatment may be beneficial to improve CPR in IVF-ET patients. Between studies homogeneity has been identified, as judged by the value I2 (0.0%). Four studies reported the data of embryo implantation [19, 22, 23, 25], and the pooled analysis did not show any beneficial effect of G-CSF treatment (RR 1.84, 95% CI 0.84–4.03, P = 0.13) (Fig. 2b). The between-study variance was relatively high in this analysis (I2 = 76.1%). However, limited reports included in our study make it impossible to further examine the variance factors, such as mete-regression analysis.
Egger regression test of the data of CPR and IR did not find any significance (P = 0.45 and 0.24, respectively) and Begg’s funnel plot showed an evident balance, indicating a low chance of publication bias (Fig. S1). Figure S2 presents the result of influence analysis after removal of individual studies, and none individual study was found to excessively influence the pooled effect for both CPR and IR analyses (Table 2).
Table 2
Judgements about risk of bias of included study
Study
Selection bias
Performance and detection bias
Attrition bias
Selective reporting
Other bias
Risk
Explanation
Risk
Explanation
Risk
Explanation
Risk
Explanation
Risk
Explanation
Aleyasin A, 2016 [25]
L
A computer-generated randomization table was used.
H
No blinding
L
No loss of follow-up
L
Not suspected
L
None
Barad DH, 2014 [19]
L
A computer-generated randomization table was used
L
Study group was blinded to patients, physicians and nurses
L
No loss of follow-up
L
Not suspected
L
None
Davari-Tanha F, 2016 [23]
L
A computer-generated randomization table was used
L
Study group was blinded to patients and clinician
L
No loss of follow-up
L
Not suspected
L
None
Eftekhar M, 2016 [22]
L
Randomization with enveloped pocket method
H
No blinding
L
No loss of follow-up
L
Not suspected
L
None
Kim CH, 2011 [30]
U
Method of random sequence allocation was not described
U
Method of blinding was not described
L
No loss of follow-up
H
Did not report implantation rate
H
Meeting abstract
Obidniak D, 2016, part I [21]
U
Method of random sequence allocation was not described
U
Method of blinding was not described
L
No loss of follow-up
H
Did not report implantation rate
H
Meeting abstract
Singh R, 2015 [20]
L
A computer-generated randomization table was used
U
Method of blinding was not described
L
No loss of follow-up
H
Did not report implantation rate
H
Meeting abstract
Scarpellini F, 2011 [31]
U
Method of random sequence allocation was not described
U
Method of blinding was not described
L
No loss of follow-up
H
Did not report implantation rate
H
Meeting abstract
Scarpellini F, 2012 [18]
U
Method of random sequence allocation was not described
U
Method of blinding was not described
L
No loss of follow-up
H
Did not report implantation rate
H
Meeting abstract
Würfel W, 2000 [16]
U
Method of random sequence allocation was not described
U
Method of blinding was not described
L
No loss of follow-up
H
Did not report implantation rate
H
Meeting abstract
U unclear, H high, L low
Subgroup analysis was further carried out according to the route of G-CSF administration (subcutaneous injection n = 5, uterine infusion n = 5, and unknown = 1) and the indications of G-CSF administration (unselected fertility n = 1, thin endometrium n = 1, and RIF n = 8). In the subgroup analysis by administration route, we found an increased CPR for both uterine infusion and subcutaneous injection, and the pooled RRs (95% CI) were 1.46 (1.04–2.05) and 2.23 (1.68–2.95), respectively (Fig. 3a). Among the studies reporting the outcome of IR, four focused on the routes of uterine infusion, and only one on the subcutaneous injection. The subgroup analysis has failed to find an increased IR after G-CSF treatment via uterine infusion (Fig. 3b). The only study with route of subcutaneous injection identified a beneficial role of G-CSF on IR [17].
In the subgroup analysis by the indications of G-CSF administration, a higher PR and IR has been found for G-CSF group as compared to the control after pooled analysis of RIF subjects, with the RRs (95% CI) 2.07 (1.64–2.61) and 1.52 (1.08–2.14), respectively. For unselected fertility or thin endometrium, only one study has been reported, and none improved PR or IR suggested for any population [19, 20].

Discussion

To data, bulks of studies have explored the benefit of G-CSF therapy for cases with RIF or unresponsive thin endometrium, or unselected patients. However, few conclusive answers can be drawn from these reports, partly due to the modest sample size, heterogeneity of administration indications or included subjects, study design, or ethnicity. Therefore, a meta-analysis is expected to provide us with more reliable and comprehensive results (Fig. 4).
Previous pooled analysis have suggested that G-CSF administration may do some good for clinical outcomes after ART treatment, however, it is still unclear which specific conditions of infertility or through which administration route does the G-CSF treatment play an beneficial role. Zhao et al. first reported the meta-analysis on this topic [32], and found an improvement in PR after G-CSF administration for infertile cases with RIF and thin endometrium, while none change in IR. Additionally, it seems that only via subcutaneous route can G-CSF administration play its beneficial role, which is contrast to the conclusion by Xie et al. [33] that only through local perfusion can G-CSF treatment improve the clinical outcome (including endometrial thickness, clinical pregnancy rate, and embryo implantation rate) after ART treatment. Another inconsistence existed in the effect of increasing endometrial thickness, while Xie et al. [33] found a statistical significance, Li et al. [34] failed to get this findings, despite that both analyses show an obvious improvement in the clinical outcome.
After quality evaluation of previous meta-analysis, it can be found that studies included for pooled analysis involved in a broad range of designs, of which the observational is the majority. Case control, cohort study, or case analysis may incur relatively greater selective bias, report bias, or confounding as compared to that of RCT. This might impair the robustness of these pooled analyses, and result in the indeterminacy in conclusion as mentioned above. Well-designed RCTs have a stronger power to control considerable biases above, and may supply a relative robust outcome. Unfortunately, the disputes still remained among available data from single RCT.
Our analysis took on a total of 10 RCTs between 2000 and 2016, involving 1016 IVF-ET cycles (521 distributed to G-CSF group, and 495 to the control), with the average ages between 31 and 39 years. From this analysis, we can conclude that G-CSF administration is able to significantly improve the CPR in total population, but it unexpectedly does not do any good for embryo implanting, the same result to the study of Zhao et al. [32]. The paradox between the roles on CPR and IR can be explained by the limited number of included studies reporting IR data (n = 4). Moreover, a significant between-study heterogeneity existed in IR analysis, and was difficult to be traced due to too few studies included (n < 5). Therefore, we must be still cautious to deal with the conclusion regarding the role on IR. To the best of our knowledge, this is the first meta-analysis pooling the data from RCTs which investigate whether G-CSF does any good for IVF patients.
We also conducted a subgroup analysis by drug route and indication of G-CSF treatment, two important factors that should be considered emphatically. The pooled analysis sub-grouped by drug route came to a conclusion that both systematic administration and local perfusion of G-CSF be beneficial for ART treatment, which is partly inconsistent with Zhao et al.’s findings [32] that uterine infusion be not an efficient route of G-CSF administration. However, another meta-analysis by Xie et al. [33] support our viewpoint that intrauterine administration can improve the clinical outcome after embryo transfer. Through more detailed comparison, it can be believed that the conclusion of our and Xie’s analysis may be more reliable due to more studies included and more strict inclusion criterion on study design or patient type.
Among all RCTs included in our analysis, most were aimed at the cases with RIF (n = 8) and suggested a substantial efficiency of G-CSF treatment after pooled analysis, while only one at thin endometrium or unselected patients in each, and neither find the beneficial effect of GSF treatment. As to the cases with thin endometrium, two previous pooled analyses have indicated that these patients may benefit from G-CSF administration, however, almost all data were derived from observational studies, and the evidence not robust enough [33, 34]. Therefore, more RCTs are still needed to clear the therapeutic effect of G-CSF on thin endometrium cases.
To data, though various therapeutic propositions for G-CSF have already been reported, the specific molecular pathways of its endometrial and embryonic action have not yet been clear. It is generally accepted that establishment and maintenance of an intrauterine immune tolerance is an integral part of maternal–fetal interface, which is requisite for successful embryo implantation [35]. The mechanism underling this immunotolerance involved a T cell helper 2 (Th-2) dominant state and Treg cell proliferation [3537]. G-CSF has been proven as a novel mediator of T cell tolerance to target at Th-2 and Treg cell [38] and play a critical role in regulation of the intrauterine immunotolerance [12, 39]. Despite limited evidence, regulating embryo development and endometrial vascular remodeling may be another two physiological roles of G-CSF as suggested by an in vitro blastocyst formation and endometrial ex vivo model test, respectively [13, 14]. Nevertheless, all above proof is just weak and preliminary, and most solitary, and increasing fundamental knowledge is expected to support the clinical applications of G-CSF in reproductive medicine.
Totally, this study is the first meta-analysis based on RCTs dealing with the role of G-CSF administration on clinical outcomes after embryo transfer. And we think the results are reliable as showed by the sensitivity and influence analysis. In conclusion, both systematic administration and local perfusion of G-CSF play a beneficial role in ART treatment, especially for the cases with RIF, but its role on the thin endometrium remains blur because insufficient data on these cases can be retrieved. Additionally, a little data about the rate of live birth can be extracted from included studies, which may impair the convincingness of this analysis.

Acknowledgements

This study was supported by the Natural Science Foundation of Zhejiang Province (LY15H260004 to L. Z., LY17H040014 to J. S. and LQ18H040004 to J. Z.), Zhejiang Medical and Health Science and Technology Plan Project (2014ZDA004 to L.Z.), National Natural Science Foundation of China (no. 81001260 to L. Z.), ‘New Century 151 Talent Program’ of Zhejiang Province (L. Z.).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://​creativecommons.​org/​licenses/​by/​4.​0/​), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Unsere Produktempfehlungen

e.Med Interdisziplinär

Kombi-Abonnement

Mit e.Med Interdisziplinär erhalten Sie Zugang zu allen CME-Fortbildungen und Fachzeitschriften auf SpringerMedizin.de. Zusätzlich können Sie eine Zeitschrift Ihrer Wahl in gedruckter Form beziehen – ohne Aufpreis.

e.Med Gynäkologie & Urologie

Kombi-Abonnement

Mit e.Med Gynäkologie & Urologie erhalten Sie Zugang zu CME-Fortbildungen der beiden Fachgebiete, den Premium-Inhalten der Fachzeitschriften, inklusive einer gedruckten gynäkologischen oder urologischen Zeitschrift Ihrer Wahl.

Zusatzmaterial
Fig S1 Egger’s publication bias plots for comparing the effect of G-CSF on CPR (a) and IR (b) in infertile women undergoing IVF/ICSI (JPEG 2995 kb)
404_2018_4892_MOESM1_ESM.jpg
Fig S2 Influence analysis of individual study on the pooled estimate for CPR (a) and IR (b). Open circle indicates the pooled OR, given named study is omitted. Horizontal lines represent the 95% CIs (JPEG 3727 kb)
404_2018_4892_MOESM2_ESM.jpg
Literatur
Über diesen Artikel

Weitere Artikel der Ausgabe 5/2018

Archives of Gynecology and Obstetrics 5/2018 Zur Ausgabe

Neu im Fachgebiet Gynäkologie und Geburtshilfe

Meistgelesene Bücher aus dem Fachgebiet

2014 | Buch

Perikonzeptionelle Frauenheilkunde

Fertilitätserhalt, Prävention und Management von Schwangerschaftsrisiken

Ein Praxisbuch für alle, die in der Beratung und Betreuung von Schwangeren und Paaren mit Kinderwunsch tätig sind. Die Herausgeber und Autoren haben alle wichtigen Informationen zusammengetragen, um Frauen sicher zu beraten, zu betreuen und kompetent Verantwortung zu übernehmen.

Herausgeber:
Christian Gnoth, Peter Mallmann

2019 | Buch

Praxisbuch Gynäkologische Onkologie

Dieses kompakte und praxisrelevante Standardwerk richtet sich alle Ärzte in Klinik und Praxis, die Patientinnen mit bösartigen Tumoren des Genitales und der Mamma behandeln. Die 5. Auflage wurde komplett aktualisiert und auf der Basis …

Herausgeber:
Prof. Dr. Edgar Petru, Dr. Daniel Fink, Prof. Dr. Ossi R. Köchli, Prof. Dr. Sibylle Loibl

Mail Icon II Newsletter

Bestellen Sie unseren kostenlosen Newsletter Update Gynäkologie und bleiben Sie gut informiert – ganz bequem per eMail.

Bildnachweise