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 Table of Contents  
EDITORIAL
Year : 2014  |  Volume : 1  |  Issue : 3  |  Page : 139-145

The unfinished story of granulocyte colony-stimulating factor in assisted reproductive technology


Rotunda-The Center For Human Reproduction, Bandra, Mumbai, India

Date of Web Publication7-Oct-2014

Correspondence Address:
Gautam Allahbadia
Rotunda-The Center For Human Reproduction, 36 Turner Road, #101 1st floor, B Wing, Bandra(West), Mumbai - 400050
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2348-2907.142318

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How to cite this article:
Allahbadia G. The unfinished story of granulocyte colony-stimulating factor in assisted reproductive technology. IVF Lite 2014;1:139-45

How to cite this URL:
Allahbadia G. The unfinished story of granulocyte colony-stimulating factor in assisted reproductive technology. IVF Lite [serial online] 2014 [cited 2022 Jan 18];1:139-45. Available from: http://www.ivflite.org/text.asp?2014/1/3/139/142318


  Introduction Top


In vitro fertilization (IVF) is expensive, elaborate, and the most successful treatment of infertility; however, the cumulative chance of having a live birth with the treatment is still around 40%. Many couples still remain unsuccessful after several IVF attempts, causing deep impact on quality-of-life, and each failed cycle causing a financial burden. Several adjuvant therapies have been used along with IVF to increase the pregnancy rates for women with repeated implantation failure. Testing of adjuvant therapies such as growth hormone, androgens, and glucocorticoids to enhance oocyte number and quality; sildenafil, low-dose aspirin, heparin, corticosteroids, and granulocyte colony-stimulating factor (G-CSF), endometrial injury, intrauterine injection of human chorionic gonadotropin, and intrauterine administration of autologous peripheral blood mononuclear cells to improve poor endometrial response; antioxidants, complementary and alternative medicine modalities, such as Chinese herbal medicine and acupuncture; and assisted hatching and preimplantation genetic screening to correct embryonic factors in properly conducted randomized controlled trials is rarely done so that potential benefits and risks are unlikely to be clearly presented to patients and clinicians.

Furthermore, many factors can impact IVF-embryo transfer (ET) success. The main independent ones are: Patient's age, Anti Mullerian hormone values and number and quality of embryos transferred. [1] It was also demonstrated a prior that endometrial thickness <7 mm negatively affects pregnancy rate. [2],[3] Moreover, Sharkey showed that immunological mechanisms in the endometrium are very important and crucial in the implantation process. [4] Some investigators demonstrated that the growth factors, hormones, and cytokines, which are produced by decidual cells, are involved in the implantation process. [5],[6] Preliminary studies demonstrated that G-CSF stimulated neutrophilic granulocyte proliferation and differentiation, acted on macrophages of decidual cells, and finally affected the implantation. [7],[8] In addition, the known and reported immune effects of G-CSF are recruitment of dendritic cells, promoting Th-2 cytokine secretion, activating T regulatory cells, and also stimulation of various proangiogenic effects. [7],[8] The receptor for G-CSF is expressed by the trophoblastic cells and by human luteinized granulosa cells. [9],[10] It is also known through previous studies that G-CSF prevents repeated miscarriages and implantation failures. [11],[12]


  Discussion Top


Culture media

The cytokine G-CSF is synthesized in the female reproductive tract and has been implicated in the growth and development of the preimplantation embryo in rodent and livestock species. To examine the effect of G-CSF on human embryo development in vitro, surplus frozen 2-4-cell embryos were cultured in media supplemented with 2 ng/ml recombinant human G-CSF. [13] The addition of cytokine increased the proportion of embryos that developed to the blastocyst stage from 30 to 76%. The developmental competence of these blastocysts, as assessed by hatching and attachment to extracellular matrix-coated culture dishes, was also improved by G-CSF. The period in culture required for 50% of the total number of blastocysts to form was reduced by 14 h, and blastocysts grown in G-CSF were found to contain approximately 35% more cells, due primarily to an increase in the size of the inner cell mass. The beneficial effect of G-CSF was exerted in each of two sequential media systems (IVF-50/S2 and G1. 2/G2.2) and was independent of the formulation of recombinant cytokine that was used. These data indicate that G-CSF may have a physiological role in promoting the development of the human embryo as it traverses the reproductive tract in vivo, and suggest that addition of this cytokine to embryo culture media may improve the yield of implantation-competent blastocysts in human IVF programs. [13]

Sjöblom et al. [13] demonstrated with in vitro experiments that the incidence of the blastulation in human embryos is increased approximately two-fold when G-CSF is present in the culture medium. In a more recent study, [14] Sjöblom et al. investigated the mechanisms underlying the embryotrophic actions of G-CSF. Using reverse transcription-polymerase chain reaction (PCR) and immunocytochemistry, expression of mRNA and protein of the G-CSF-receptor alpha subunit (GM-Ralpha) was detected in embryos from the first-cleavage through blastocyst stages of development, but the G-CSF-receptor beta common subunit (betac) could not be detected at any stage. When neutralizing antibodies reactive with GM-Ralpha were added to embryo culture experiments, the development-promoting effect of G-CSF was ablated. In contrast, G-CSF activity in embryos was not inhibited either by antibodies to betac or by E21R, a synthetic G-CSF analog that acts to antagonize betac-mediated G-CSF signaling. Unexpectedly, E21R was found to mimic native G-CSF in promoting blastulation. When embryos were assessed for apoptosis and cell number by confocal microscopy after TUNEL and propidium iodine staining, it was found that blastocysts cultured in G-CSF contained 50% fewer apoptotic nuclei and 30% more viable inner cell mass cells. Together, these data indicate that G-CSF regulates cell viability in human embryos and that this potentially occurs through a novel receptor mechanism that is independent of betac. [14]

Spandorfer et al. set up a study to determine whether G-CSF produced by autologous endometrial co-culture was associated with an improved outcome in 53 patients with a history of multiple IVF failures. [15] The conditioned media from endometrial co-culture cells exposed or nonexposed to human embryos was analyzed for G-CSF. Exposure or nonexposure to an embryo did not result in an enhancement of G-CSF production. Insignificant levels of G-CSF were determined from media alone. Receiver operating characteristic (ROC) analysis revealed that levels of G-CSF from supernatants of endometrial co-culture exposed to embryos that measured below 130 pg/ml reflected a diminished prognosis (5/17 had a positive pregnancy vs. 21/36 with G-CSF levels >130 pg/ml; P < 0.05). [15] The improved outcome associated with G-CSF values >130 pg/ml may reflect: (1) A direct positive effect of G-CSF; (2) an embryotropic factor up-regulated by G-CSF; or, (3) that G-CSF functions as a marker for the importance of the glandular component in endometrial co-culture systems.

Ziebe et al. published a multicenter, randomized, placebo-controlled, double-blinded prospective study evaluating the effect of G-CSF in embryo culture medium on ongoing implantation rate (OIR). [16] Fourteen Scandinavian fertility clinics participated in this study. A total of 1,332 women with indication for IVF or intracytoplasmic sperm injection (ICSI); 1,149 received ET (G-CSF: N = 564; control: N = 585). Oocytes were fertilized, and embryos cultured and transferred in control medium or test medium containing 2 ng/mL G-CSF. The endpoints of the study were OIR at gestational week 7, with follow-up at week 12 and birth. At week 7, OIRs were 23.5% (G-CSF), and 20.0% (control) (odds ratio [OR]: 1.26, 95% confidence interval [CI]: 0.91-1.75). At week 12, OIRs were 23.0% (G-CSF) and 18.7% (control) (OR: 1.35, 95% CI: 1.06-1.72), and live birth rates were 28.9% and 24.1%, respectively (OR: 1.35, 95% CI: 1.03-1.78). The effect of G-CSF was influenced by the human serum albumin concentration in the medium. Birth weight and an abnormality incidence were similar in both groups. Exploratory analyses showed that G-CSF increased OIR in women with previous miscarriage, especially in women with more than one miscarriage. The research paper concluded that the addition of G-CSF to embryo culture medium elicits a significant increase in survival of transferred embryos to week 12 and live birth. [16] These results are consistent with a protective effect of G-CSF on culture-induced embryo stress. G-CSF may be particularly efficacious in women with previous miscarriage. [16]

Addition of recombinant G-CSF to the culture medium can make human embryo culture more akin to in vivo conditions and improve the efficacy of assisted reproductive technology (ART) cycles (T17). The analysis of cultured embryos in EmbryoGen medium containing  G-CSF has shown that fertilization rate, embryo culture and transfer to patients with previous unsuccessful attempts increases clinical pregnancy rate compared to the control group 39.1 versus 27.8%, respectively. [17] It was noted that the implantation rate (IR) (on 7 weeks' gestation) and progressive clinical pregnancy rate (on 12 weeks' gestation) were significantly higher in group embryos cultured in EmbryoGen medium compared with standard combination of medium (ISM1 + VA), and were 20.4 and 17.4% versus 11.6 and 9.1%, respectively. [17]

Follicular fluid

From a total sample of 93 patients, Salmassi et al. analyzed in group 1 (n = 82) the level of G-CSF and estradiol (E (2)) in serum and follicular fluid (FF) on the day of follicular puncture (FP). [9] Furthermore, in response to ovarian stimulation, G-CSF levels in serum were compared between low (n = 11), moderate (n = 53) and high (n = 18) response patients. In group 2 (n = 23) serum for G-CSF assessment was collected throughout the menstrual cycle until gestation. Group 3 (n = 11) patients with endometriosis were assessed for G-CSF in serum and FF on day of FP without further differentiation. G-CSF in FF was higher than in serum (P < 0.01). G-CSF in serum increased from low through moderate to high response (P < 0.001); pregnancy rates were 0, 24.5 and 33.5% respectively. G-CSF in serum increased throughout the stimulation, reached a peak with ovulation induction (P = 0.01) and decreased until ET (P = 0.001). G-CSF level only in pregnant patients (n = 11) increased from ET to implantation to gestation (P = 0.005). In endometriosis patients, G-CSF in serum and FF was lower than in nonendometriosis patients (P ≤ 0.03) and corresponded with low response patients. G-CSF is involved in follicle development and may be a predictor of IVF outcome. [9]

To evaluate the requirements for routine FF G-CSF quantification, Lιdιe et al. [18] compared FF G-CSF measurements made with two multiplexed microbead assays purchased from Bio-Rad Laboratories and R and D Systems, and a commercial  G-CSF ELISA (R and D Systems). Individual FFs (n = 139) associated with transferred embryos were analyzed to determine cytokine profile and the fate of each transferred embryo was recorded. The effect of multiplexing as well as comparison of the respective performances of the microbead assay with a flow cytometry assay was explored. The quantification of FF G-CSF using microbead assay methodologies, but not ELISA, yielded results showing the utility of FF G-CSF as a biomarker predictive of a successful delivery (area under ROC [AUC] (ROC): 0.77 [0.68-0.84] [P = 0.003] and 0.75 [0.66-0.82] [P = 0.004] for Bio-Rad and R and D Systems microbead assays respectively), whereas FF G-CSF values quantified by ELISA were not predictive (AUC (ROC):0.61 [0.52-0.70] P = 0.84). [18]

Identification of biomarkers of optimal uterine receptivity to the implanting embryo, as well as biomarkers of oocyte competence, would undoubtedly improve the efficiency of ART. Expression of interleukin-15 (IL-15) and IL-18 has been shown to be different in patients with failed implantation after IVF/ICSI compared with fertile controls and both correlate with local uNK (CD56 + ) recruitment and angiogenesis. [19] Tumor necrosis factor weak inducer of apoptosis (TWEAK) has been described in mice as a potent early immune regulator able to protect the conceptus. The results of recent French studies in humans suggest that TWEAK modulates the IL-18 related cytotoxicity of uNK cells. [18] Quantification of IL-18, TWEAK and IL-15 mRNA expression by real-time PCR in endometrial tissue collected in mid-luteal phase of nonconception cycles allowed documentation of physiological events that occur at the time of uterine receptivity. [19] Such information may be useful for the physician especially in patients where embryos fail to implant.

The same French group next set-up a study to explore oocyte competence for the subsequent birth. [20] The modified natural IVF/ICSI cycle was used as an experimental model by measuring levels of cytokines, chemokines, and growth factors in individual FFs. [20] Single FF from 83 women was analyzed during a modified natural IVF/ICSI cycle, and reproducibility of follicular composition was evaluated over two cycles for 15 patients. Each FF sample was blindly tested to assess levels of 26 factors by bead-based immunoassays. Each mediator was evaluated as a potential biomarker of subsequent birth by multivariate regression analysis. A combination of both FF G-CSF and IL-15 was the optimal model to predict birth (AUC (ROC), 0.85). Birth rates per cycle were 48.9% (16/33) if two good-prognosis criteria were present (FF G-CSF >12 pg/mL and IL-15 <7 pg/mL) and 8% (3/36) and 0% (0/14) if, respectively, one or none were present. FF G-CSF was significantly correlated over two cycles (r = 0.71), suggesting a possible prognostic value of its documentation. [20] Combined follicular G-CSF and IL-15 quantification appears as an efficient and noninvasive method to define oocyte competence for subsequent successful conception in modified natural IVF/ICSI cycles. [20]

Previous experiments had shown that G-CSF, quantified in the FF of individual oocytes, correlates with the potential for an ongoing pregnancy of the corresponding fertilized oocytes among selected transferred embryos. [18],[20] Lιdιe et al. set up a proof of concept study aimed at evaluating the impact of including FF G-CSF quantification in the ET decisions. [21] FF G-CSF was quantified with the Luminex XMap technology in 523 individual FF samples corresponding to 116 fresh transferred embryos, 275 frozen embryos and 131 destroyed embryos from 78 patients undergoing ICSI. Follicular G-CSF was highly predictive of subsequent implantation. The receiving operator characteristics curve methodology showed its higher discriminatory power to predict ongoing pregnancy in multivariate logistic regression analysis for FF G-CSF compared with embryo morphology (0.77 [0.69-0.83], P < 0.001 vs. 0.66 [0.58-0.73], P = 0.01). Embryos were classified by their FF G-CSF concentration: Class I over 30 pg/ml (a highest positive predictive value for implantation), Class II from 30 to 18.4 pg/ml and Class III < 18.4 pg/ml (a highest negative predictive value). Embryos derived from Class I follicles had a significantly higher IR than those from Class II and III follicles (36 vs. 16.6 and 6%, P < 0.001). Embryos derived from Class I follicles with an optimal morphology reached an IR of 54%. Frozen-thawed embryos transfer derived from Class I follicles had an IR of 37% significantly higher than those from Class II and III follicles, respectively, of 8 and 5% (P < 0.001). 35% of the frozen embryos, but also 10% of the destroyed embryos were derived from G-CSF Class I follicles. Nonoptimal embryos appear to have been transferred in 28% (22/78) of the women, and their pregnancy rate was significantly lower than that of women who received at least one optimal embryo (18 vs. 36%, P = 0.04). They concluded that monitoring FF G-CSF for the selection of embryos with a better potential for pregnancy might improve the effectiveness of IVF by reducing the time and cost required for obtaining a pregnancy. [21]

Endometrium

Proliferative and secretory changes at the endometrial lining are the result of a complex intrauterine environment where sex steroid hormones and different local factors play an important role for endometrial thickening. Optimal endometrial thickness reflects an adequate maturation, which is a key factor for embryo implantation. Lucena and Moreno-Ortiz presented a case of a woman with polycystic ovary who was treated using in vitro maturation techniques. [22] In addition, this patient showed a dys-synchrony between the endometrial phase characterized by endometrial thinning and the embryo development which had a negative impact for embryo implantation. A protocol using uterine perfusion of G-CSF was performed as an alternative treatment for the unresponsive endometrium. [22] They found that the uterine infusion of G-CSF quickly increased endometrial thickness resulting in a successful pregnancy and healthy born baby. These results suggested that G-CSF is a factor that participates during endometrial remodeling enhancing the synchronization between uterine environment and embryo development. [22]

Li et al. aimed to evaluate the effectiveness of G-CSF administration for infertile women with a thin endometrium in a frozen ET program. [23] Among 59 infertile patients with a 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, with 80 cycles defined as the control group. The IR and clinical pregnancy rate per ET were similar in all the groups (P > 0.05). This study failed to demonstrate that G-CSF has the potential to improve embryo implantation and clinical pregnancy rate of the infertile women with a thin endometrium. [23]

Gleicher et al. set-up a prospective cohort study of four patients to assess whether inadequate, thin endometrium (<7 mm), after failure to expand with standard treatment options, will be responsive to cytokine treatment. [24] Four consecutive women are undergoing IVF who, after standard endometrial preparation, still demonstrated highly inadequate endometrium were given a transvaginal endometrial perfusion with G-CSF. They reported successful endometrial expansion to at least minimal thickness of 7 mm after uterine perfusion with G-CSF in four patients previously resistant to treatment with estrogen and vasodilators. All four patients, therefore, reached ET, and all four also conceived, although one pregnancy required termination because of intramural, cornual ectopic location. Endometrial expansion to minimal thickness occurred within approximately 48 h from infusion. Uterine perfusion with G-CSF represents a promising new tool for the currently mostly intractable problem of inadequate, thin endometrium. [24]

A single uterine infusion of G-CSF was performed in the late proliferative phase in a woman with a double uterus who only attained a 5-mm thickness despite a high dose vaginal and oral estradiol regimen plus sildenafil. [25] No increase was found within a couple days. A previous four-case study in another institution had found 100% improvement in the endometrial thickness in women with consistently thin endometria. [24] Perhaps the uterine anomaly in the present case prevented the response of the endometrium. [25]

Barad et al. [26] investigated whether G-CSF affects endometrial thickness, IRs, and clinical pregnancy rates in routine, unselected IVF cycles. They registered an individually randomized, two-group, parallel double-blinded placebo-controlled clinical trial. The trial included 141 consecutive, unselected, consenting women with no history of renal disease, sickle cell disease, or malignancy who were undergoing IVF. Sealed, numbered, opaque envelopes assigned 73 patients to receive G-CSF (Filgrastim, Amgen, 300 μg/1.0 mL) and 68 to receive placebo (saline). The main outcome measures set-up were endometrial thickness, clinical pregnancy, and embryo IRs. The mean age for the whole study group was 39.59 ± 5.56 years (G-CSF: 39.79 ± 5.13 years; placebo: 39.38 ± 6.03 years). Endometrial thickness statistically significantly increased over the 5-day observation period for the whole group by approximately 1.36 mm. The increase in the G-CSF group was not statistically significantly different from the control group. Statistical models looking at treatment effects on clinical pregnancy and IRs demonstrated no effect of G-CSF treatment. There were no adverse events for either treatment group. The study concluded that in normal IVF patients, G-CSF does not affect endometrial thickness, IRs, or clinical pregnancy rates. Because these results were obtained in an older patient population, they may not necessarily apply to younger women. [26]

Gleicher et al. [27] set-up a study to find out if thin endometrium unresponsive to standard treatments expands by intrauterine perfusion with G-CSF. In this prospective observational cohort pilot study over 18 months, they described 21 consecutive infertile women with endometria <7 mm on the day of hCG administration in their first IVF cycles at their center. All previous cycles using traditional treatments with estradiol, sildenafil citrate (Viagra™) and/or beta-blockers had been unsuccessful. G-CSF (Nupogen™) was administered per intrauterine catheter by slow infusion before noon on the day of hCG administration. If the endometrium had not reached at least a 7-mm within 48 h, a second infusion was given following oocyte retrieval. Primary and secondary main outcomes were an increase in endometrial thickness and clinical pregnancy, respectively. Endometrial thickness was assessed by vaginal ultrasound at the most expanded area of the endometrial stripe. This study was uncontrolled, each patient serving as her own control in a prospective evaluation of endometrial thickness. The mean ± standard deviation age of the cohort was 40.5 ± 6.6 years, gravidity was 1.8 ± 2.1 (range: 0-7) and parity was 0.4 ± 1.1 (range: 0-4); 76.2% of women had, based on age-specific follicle-stimulating hormone and anti-Müllerian hormone, an objective diagnosis of diminished ovarian reserve and had failed 2.0 ± 2.1 prior IVF cycles elsewhere. With 5.2 ± 1.9 days between G-CSF perfusions and ETs, endometrial thickness increased from 6.4 ± 1.4 to 9.3 ± 2.1 mm (P < 0.001). The difference in change was 2.9 ± 2.0 mm, and did not vary between conception and nonconception cycles. About 19.1% ongoing clinical pregnancy rate was observed, excluding one ectopic pregnancy. According to the authors, this pilot study supported the utility of G-CSF in the treatment of chronically thin endometrium and suggested that such treatment will, in very adversely affected patients, result in low but very reasonable clinical pregnancy rates. [27]

The aim of Kunicki et al.'s study was to assess the G-CSF effects on unresponsive thin (<7 mm) endometrium in women undergoing IVF. [28] They included thirty-seven subjects who had thin unresponsive endometrium on the day of triggering ovulation. These patients also failed to achieve an adequate endometrial thickness in at least one of their previous IVF cycles. In all the subjects at the time of infusion of G-CSF, endometrial thickness was 6.74 ± 1.75 mm, and after infusion, it increased significantly to 8.42 ± 1.73 mm. When they divided the group into two subgroups according to whether the examined women conceived, they showed that the endometrium expanded significantly from 6.86 ± 1.65 to 8.80 ± 1.14 mm in the first group (who conceived) and from 6.71 ± 1.80 to 8.33 ± 1.85 mm in the second, respectively. There were no significant differences between the two subgroups in respect to the endometrial thickness both before and after G-CSF infusion. The clinical pregnancy rate was 18.9%. They concluded that the infusion of G-CSF leads to the improvement of endometrium thickness after 72 h. [28]


  Conclusions Top


Only 5% of oocytes lead to a live birth after IVF. [18] Currently, it is difficult to evaluate oocyte quality on the sole basis of morphology criteria. Embryo morphology is considered as a good marker of potential implantation; however, it is not enough. Therefore, we need to develop a good noninvasive assessment of oocyte quality. Research performed on FF may represent a new tool of increasing interest. [18],[19],[20],[21] The presence of G-CSF in FF could predict ongoing pregnancy. [18],[19],[20],[21]

Cytokine quantification may assist in understanding the mechanisms leading to repeated IVF/ICSI failure: Either depletion of cytokines necessary for the apposition-adhesion or an excess of cytokines leading to local cytotoxicity, may impair the implantation of the embryo. [18],[19],[20],[21] Other new data suggest that a preconception dialog mediated by the oocyte and the FF and the oocyte may contribute to later implantation success. [18],[19],[20],[21] Follicular concentration of G-CSF appears as a useful biomarker of oocyte competence before fertilization. G-CSF in individual FFs correlates with the potential of the corresponding embryo to result in a live birth after transfer in IVF. [20],[21] Moreover both in human and animal models, evidence of a role of the endometrium as a biosensor of the embryo is emerging.

A thin endometrium is one of the most difficult problems encountered in assisted reproduction every day practice. Several methods were proposed, to increase thin endometrium in women undergoing IVF. These therapies included tocopherol, pentoxifylline, low-dose aspirin, sildenafil citrate, estradiol administration and hCG priming. [29],[30],[31],[32] Endometrial perfusion with G-CSF may be effective in expanding chronically unresponsive thin endometrium, which was resistant to traditional remedies. [24],[26],[27],[28] This treatment also deserves further investigation for its potential to improve implantation chances in association with IVF and, therefore, pregnancy rates.

 
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  Authors Top


Gautam N. Allahbadia, MD is the Editor-in-chief of the Journal of Obstetrics and Gynecology of India as well as the IVF Lite (Journal of Minimal Stimulation IVF). He is the Medical Director of Rotunda -The Center for Human Reproduction, the World-renowned Fertility Clinic at Bandra, Mumbai, India as also the New Hope IVF Clinic at Sharjah, UAE. He is a noted world authority on ultrasound guided embryo transfers and one of the pioneers in Third Party Reproduction in South-East Asia. Dr. Allahbadia was responsible for India's first trans-ethnic surrogate pregnancy involving a Chinese couple's baby delivered by an unrelated Indian surrogate mother. He has over 100 peer-reviewed publications to his credit and is on the editorial board of several international journals. Throughout his career, Dr. Allahbadia has been instrumental in developing new fertility enhancing protocols and propagating the use of ultrasound in embryo transfer procedures. You can read more about his work at www.gautamallahbadia.com.



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