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Showing 17 results for Artificial

Fatemeh Nayeri, Marzieh Aghahosseini, Ashraf Alyasin, Firoozeh Nili,
Volume 4, Issue 2 (7-2006)

Background: Today there is a rise in the number of newborns conceived by artificial reproductive techniques (ART). Numerous studies have been performed on the perinatal outcome of these pregnancies. However, there is limited data about the condition of health of these newborns in Iran. Objective: Regarding the higher prevalence of probable complications and symptomatic congenital anomalies, we aimed to determine the state of health of newborns born by ART.
Materials and methods: A total of 109 newborn who were conceived through ART and 479 newborns of spontaneous conception were enrolled into our study. The study was prospective, case-control study in Tehran, Iran, from March 2003 to March 2004. Both case and control groups were adjusted in regard to race, sex, type of delivery, chronic disease of mother, age of mother, and antenatal steroids administration. All newborns were examined by neonatologist after birth and their outcome were followed until hospital discharge or death. Data pertaining to clinical and laboratory findings of newborns and death were entered into a questionnaire and subsequently analyzed by appropriate statistical tests. Confidence interval was 95%.
Results : Prematurity, low birth weight (LBW), very low birth weight (VLBW), twins and triplets, small for gestational age (SGA), need for resuscitation at birth, respiratory distress syndrome (RDS) and NICU admission were significantly higher among newborns born after ART than those born through spontaneous conception (p<0.05). Regression logistic analysis showed that RDS and NICU admission were more strongly associated with weight at birth and gestational age than with method of conception. However, increased rate of SGA in the case group was associated with multiple pregnancy. Also, there was no significant statistical relationship between the method of conception and the prevalence of congenital anomalies, large for gestational age (LGA), congenital pneumonia, necrotizing entrocolitis (NEC), respiratory air leakage syndromes (ALS), hydrops fetalis, hyperbilirubinemia sepsis, meconium aspiration syndrome (MAS), isseminated intravascular coagulopathy (DIC), cardiac failure, lung hemorrhage, hypoglycemia, hypocalcemia, neutropenia, thrombocytopenia and hemolysis.
Conclusion: Newborns who were conceived by ART were more likely in need of resuscitation at birth regardless of other factors. Furthermore, newborns born after ART were at higher risk of developing prematur birth, LBW, and multiple birth.
Elke Heytens, Reza Soleimani, Petra de Sutter,
Volume 6, Issue 5 (7-2008)

Fertilization is triggered by changes in intracellular calcium concentration. In mammals, these transients in ooplasmic calcium concentration take the form of repetitive spikes, so called calcium oscillations (Ca2+-oscillations). These oscillations are important for relieve of meiotic arrest and to induce all the other events of oocyte activation. Although a surface mediated way of oocyte activation has been proposed, there is now substantial evidence to suggest that the sperm cell induces these Ca2+-oscillations by introducing a sperm specific phospholipase C, PLCζ, in the ooplasm. Ca2+-oscillations are also observed after intracytoplasmic sperm injection (ICSI), a successful technique in human assisted reproduction. In the rare cases that no fertilization is observed following ICSI, this may be due to a deficiency in PLCζ. However, artificial activating the oocytes after ICSI by increasing the calcium concentration can restore fertilization rates in these cases and support further development, as evidenced by successful pregnancies. Further evaluation of the current protocols for assisted oocyte activation is appropriate and investigation of the future application of PLCζ is warranted.
Seyyed Mojtaba Yassini, Mohsen Taghavi Shavazi, Naeimeh Taghavi Shavazi,
Volume 10, Issue 5 (10-2012)

Background: Nowadays artificially assisted reproductive techniques are used to cure infertility. These methods are highly expensive, time-consuming and have low success rates which are usually around 20-40%. One of the best alternate methods for infertility treatment that can be considered is adoption that often decreases the treatment costs and the psychological impact within an infertile couple.
Objective: This study has been done with the aim of determining adoption acceptance rates and the effective factors of adoption in infertile couples. Materials and Methods: A cross-sectional study was performed between October 2009-2010 on 200 infertile couples who had been referred to Infertility Center of Shahid Sadoughi University of Medical Sciences. Information gathered through face-to-face interview and questionnaires. The data analyzed through a SPSS software program using ANOVA test.
Results: There was a significant statistical relationship between adoption acceptance value scores and marriage duration of a couple (p=0.002 in men, p=0.004 in women) and presence of adoption backgrounds in male relatives (p=0.004). There was no statistically significant relationship between age, gender, education level, and onus of infertility, the number of previous referrals for an infertility solution and presence of adoption backgrounds in female relatives.
Conclusion: Adoption as an alternative option to infertility treatment need to be more considered as a medical, social and cultural issue.
Liu Xuemei, Yue Jing, Xu Bei, Hu Juan, Ren Xinling, Liu Qun, Zhu Guijin,
Volume 11, Issue 11 (12-2013)

Background: Creation of artificial gametes may provide a universal solution for these patients of lacking gametes. Stem cell technology may provide a way to obtain fully functional gametes. Retinoic acid (RA) can initiate meiosis. Several studies have demonstrated that RA can promote sperm cells differentiation from mouse embryonic stem cells (mESCs) and other cells from human embryonic stem cells (hESCs).
Objective: We sought to determine whether RA could promote differentiation of germ cells from hESCs.
Materials and Methods: hESCs were differentiated as embryoid bodies (EBs) in suspension with all-trans RA (atRA) or without atRA for 0, 1, 3, 5 and 7 days, and then compared the expression of VASA, SCP3, GDF9 and TEKT1 by real-time PCR. The statistical differences were evaluated by one way ANOVA.
Results: The expression of germ cell-specific markers including the gonocyte marker VASA, the meiotic marker SCP3, and postmeiotic markers, GDF9 and TEKT1, all increased in the presence and absence of RA as EB differentiation progressed. In addition, the expression of these markers increased an average of 9.3, 6.9, 7.2 and 11.8 fold respectively in the presence of RA, compared to the absence of RA, over 5 days differentiation.
Conclusion: Our results indicate that hESCs may have the potential to differentiate to primordial germ cells (PGCs) and early gametes. And RA can improve germ cells differentiation from hESCs.
Maryam Eftekhar, Sima Janati, Mozhgan Rahsepar, Abbas Aflatoonian,
Volume 11, Issue 11 (12-2013)

Background: Chemical activation is the most frequently used method for artificial oocyte activation (AOA), results in high fertilization rate.
Objective: This prospective, randomized, unblinded, clinical study aimed to evaluate the efficiency of oocyte activation with calcium ionophore on fertilization  and pregnancy rate after intracytoplasmic sperm injection (ICSI) in infertile men suffer from teratoospermia.
Materials and Methods: Thirty eight women with teratoospermic partner underwent ICSI with antagonist protocol. A total of 313 metaphase II (MII) oocytes were randomly divided into two groups: In the oocytes of the control group (n=145), routine ICSI was applied. Oocytes in the AOA group (n=168) immediately after ICSI, were entered in culture medium supplemented with 5 μΜ calcium ionophore (A23187) for 5 minutes and then washed at least five times with MOPS solution. In both groups, the fertilization was evaluated 16-18 hours after ICSI.
Results: The number of fertilized oocytes and embryos obtained were significantly different between two groups (p=0.04). There was no significant difference between the two studied groups regarding the fertilization and cleavage rate (95.33% vs. 84.4%, p=0.11; and 89.56% vs. 87.74%, p=0.76, respectively). Implantation rate was higher in AOA group than in control group, but the difference was not significant (17.64% vs. 7.4%, p=0.14). No significant differences were observed in chemical and clinical pregnancy rate between groups (47.1% vs. 16.7%, p=0.07; and 41.2% vs. 16.7%; p=0.14, respectively).
Conclusion: We didn’t find significant difference in the implantation, fertilization, cleavage and pregnancy rates between the two groups but could significantly increase the number of fertilized oocytes and embryos obtained. Finally oocyte activation with calcium ionophore may improve ICSI outcomes in infertile men suffer from teratoospermia. Further study with more cases can provide greater value.
Mohammad Reza Moein, Serajedin Vahidi, Jalal Ghasemzadeh, Nasim Tabibnejad,
Volume 12, Issue 5 (6-2014)

Background: Male are involved in near 50% of cases of infertility and reactive oxygen species (ROS) playing an important role in decreasing fertility potential. Accurate measurement of ROS seems to be important in evaluation of infertile male patients.
Objective: To compare ROS measurement in neat and washed semen samples of infertile men and define the best method for evaluation of ROS in these patients.
Materials and Methods: We measured the level of ROS in semen samples of thirty five non-azoospermic men with infertility. The semen samples were divided into two parts and the semen parameters and ROS levels in neat and washed samples were evaluated. We also evaluated the presence of pyospermia using peroxidase test.
Results: The differences regarding sperm count and quick motility were significant in neat and washed semen samples. The mean ROS level was significantly higher in neat samples compared with washed spermatozoa (7.50 RLU vs. 1.20 RLU respectively). Difference in ROS levels was more significant in patients with pyospermia compared to whom with no pyospermia (378.67 RLU vs. 9.48 RLU respectively).
Conclusion: Our study confirmed that neat or unprocessed samples are better index of normal oxidative status of semen samples. Because we do not artificially add or remove factors that may play an important role in oxidative equilibrium status.
Marzieh Rahimipour, Ali Reza Talebi, Morteza Anvari, Abolghasem Abbasi Sarcheshmeh, Marjan Omidi,
Volume 12, Issue 5 (6-2014)

Background: Saccharin is an artificial non-caloric sweetener that used to sweeten products such as drinks, candies, medicines, and toothpaste, but our bodies cannot metabolize it. Sodium saccharin is considered as an important factor in tumor promotion in male rats but not in humans.
Objective: The objective of this study was to investigate the effect of saccharin consumption on sperm parameters and apoptosis in adult mice.
Materials and Methods: Totally 14 adult male mice were divided into 2 groups. Group 1 served as control fed on basal diet and group 2 or experimental animals received distilled water containing saccharin (0.2% w/v) for 35 days. After that, the left cauda epididymis of each mouse was cut and placed in Ham’s F10. Swimmed-out spermatozoa were used to analyze count, motility, morphology (Pap-staining) and viability (eosin-Y staining). Sperm DNA integrity, as an indicator of apoptosis, was assessed by SCD (sperm chromatin dispersion) and terminal deoxynucleotidyl transferase (TUNEL) assay.
Results: Following saccharin consumption, we had a reduction in sperm motility with respect to control animals (p=0.000). In addition, the sperm count diminished (17.70±1.11 in controls vs. 12.80±2.79 in case group, p=0.003) and the rate of sperm normal morphology decreased from 77.00±6.40 in control animals into 63.85±6.81 in saccharin-treated mice (p=0.001). Also, we saw a statistically significant increase in rates of sperm DNA damage and apoptosis in experimental group when compared to control one (p=0.001, p=0.002 respectively).
Conclusion: Saccharin consumption may have negative effects on sperm parameters, and increases the rate of sperm DNA fragmentation and apoptosis in mice.

Ahmed M. Isa, Basim Abu-Rafea, Sahel Al-Asiri, Johara Al-Motawa,
Volume 12, Issue 7 (8-2014)

Background: Intrauterine Insemination (IUI) remains the first thought of infertility treatment.
Objective: To compare the stimulation effects and Pregnancy rate (PR) outcomes of two ovulation induction (OI) medications, human-derived menopausal gonadotrophins (hMGH), Merional (MER), and recombinant follicular stimulating hormone (rFSH), Puregon (PUR), in a cohort of Saudi infertile patients, for better predictability of treatment results.
Materials and Methods: During a 24-month period, 296 women underwent IUI single treatments. PR’s were correlated with the type of stimulation medication that were prospectively and randomly assigned to each patient, and with the number and size of maturing follicles detected on the hCG injection day.
Results: MER and PUR needed comparable number of days (9.26±4.74 and 9.73±6.27 respectively) before follicles were ready for IUI, although the average amount used from MER, 1199.90 IU, was about double that was used from PUR, 621.08 IU. The overall PR in case of PUR however was nearly double that of MER, 13.28% and 7.14% respectively. The best PR, 16.22%, occurred when the follicles matured within 12-13 days. Three follicles of at least 15-mm diameter on the hCG day had better PR’s than one or two, however when the follicles’ diameters were at least 18-mm, PR was significantly higher, (p=0.013).
Conclusion: MER and PUR had comparable stimulation effects; however PUR had noticeably higher PR. The best PR occurred when the follicles matured within 12-13 days. PR in case of three maturing follicles on the hCG day was better than only one or two, and significantly better when their diameters were at least 18 mm.
Arash Khaki,
Volume 13, Issue 3 (3-2015)

Background: Antibiotic therapies used in treatment of many diseases have adverse effects on fertility. This review analyzes previous comparative studies that surveyed the effects of two common groups of antibiotics on male fertility.
Objective: To evaluate histo-pathological effects of fluoroquinolones and aminoglycosides on sperm parameters and male reproductive tissue.
Materials and Methods: Articles about the effects of aminoglycosides and fluoroquinolones on male infertility, sperm parameters, male reproductive tissue, and spermatogenesis in English and Persian languages published on Google Scholar and PubMed databases from January 2000 to December 2013 were assessed. Randomized controlled trials (RCTs) assessing the effects of aminoglycosides or fluoroquinolones on sperm parameters, artificial insemination, and male reproductive tract or RCTs comparing aminoglycosides vs. fluoroquinolones were eligible for inclusion. For ascertaining the reliability of study, data were extracted independently and in duplicate by two investigators.
Results: Sperm viability was decreased significantly with streptomycin, gentamicin, and neomycin (p<0.001). Sperm motility was decreased significantly with gentamicin and neomycin (p<0.05). Total sperm count was significantly decreased with ofloxacin, gentamicin, streptomycin, and neomycin (p<0.022). There was significant decrease in post-thawing motility with low dose and high dose of ciprofloxacin. Testis weight was decreased with gentamicin and ofloxacin significantly (p<0.011). There was significant decrease in seminal vesicle weight with gentamicin, neomycin, and ofloxacin (p<0.022). Furthermore, changes in epididymis weight, percentage of total apoptotic cells, and diameter of seminiferous tubule were significant with all drugs including streptomycin, gentamicin, neomycin, and ofloxacin (p<0.05).
Conclusion: Streptomycin has less negative effects on cell’s apoptosis and sperm parameters as compared to other drugs. Gentamicin has more detrimental effects so lesser dosage and duration is recommended. Fluoroquinolones showed negative effects on testis tissue and sperm parameters. Ciprofloxacin has less adverse effects than gentamicin in artificial insemination.
Negar Ghazi, Mohammad Arjmand, Ziba Akbari, Ali Owsat Mellati, Hamid Saheb-Kashaf, Zahra Zamani,
Volume 14, Issue 1 (1-2016)

Background: So far, non-invasive diagnostic approaches such as ultrasound, magnetic resonance imaging, or blood tests do not have sufficient diagnostic power for endometriosis disease. Lack of a non-invasive diagnostic test contributes to the long delay between onset of symptoms and diagnosis of endometriosis.
Objective: The present study focuses on the identification of predictive biomarkers in serum by pattern recognition techniques and uses partial least square discriminant analysis, multi-layer feed forward artificial neural networks (ANNs) and quadratic discriminant analysis (QDA) modeling tools for the early diagnosis of endometriosis in a minimally invasive manner by 1H- NMR based metabolomics.
Materials and Methods: This prospective cohort study was done in Pasteur Institute, Iran in June 2013. Serum samples of 31 infertile women with endometriosis (stage II and III) who confirmed by diagnostic laparoscopy and 15 normal women were collected and analyzed by nuclear magnetic resonance spectroscopy. The model was built by using partial least square discriminant analysis, QDA, and ANNs to determine classifier metabolites for early prediction risk of disease.
Results: The levels of 2- methoxyestron, 2-methoxy estradiol, dehydroepiandrostion androstendione, aldosterone, and deoxy corticosterone were enhanced significantly in infertile group. While cholesterol and primary bile acids levels were decreased. QDA model showed significant difference between two study groups. Positive and negative predict value levels obtained about 71% and 78%, respectively. ANNs provided also criteria for detection of endometriosis.
Conclusion: The QDA and ANNs modeling can be used as computational tools in noninvasive diagnose of endometriosis. However, the model designed by QDA methods is more efficient compared to ANNs in diagnosis of endometriosis patients.
Saghar Salehpour, Marzieh Zamaniyan, Nasrin Saharkhiz, Shahrzad Zadeh Modares, Sedighe Hosieni, Samira Seif, Narges Malih, Parinaz Rezapoor, Mohammad-Reza Sohrabi,
Volume 14, Issue 9 (9-2016)

Background: Recurrent implantation failure is one of the most issues in IVF cycles.Some researchers found that beneficial effects of endometrial Scratching in womenwith recurrent implantation failure, while some authors demonstrated contrary results
Objective: The present study aimed to investigate the effect of intrauterine. Salineinfusion as a form of endometrial injury, during fresh in vitro fertilization-embryotransfer cycle, among patients with recurrent implantation failure.
Materials and Methods: In this clinical trial study 63 women undergoing assistedreproductive technology were divided into two groups either local endometrialinjury by intrauterine saline infusion during day 3-5 of the ongoing controlledovarian stimulation cycle, or IVF protocol performed without any other interventionin Taleghani Hospital, Tehran, Iran. The main outcome measure was clinicalpregnancy rates.
Results: Patients who received intra uterine saline infusion (n=20), had significantlylower clinical pregnancy numbers (1 vs. 9, p<0.05) and implantation rates (4.7% vs.41.6%, p<0.05), compared to controls (n=39). However, there was no significantdifference in miscarriage rates (9.4% vs. 8.7%, p>0.05) and multiple pregnancynumbers (1 vs. 3, p>0.05) between groups.
Conclusion: When intrauterine saline infusion as a form of endometrial injury isperformed during the ongoing IVF cycles it has negative effect on reproductiveoutcomes among patients with recurrent implantation failure.
Ashraf Aleyasin, Marzieh Aghahosseini, Leili Safdarian, Maryam Noorzadeh, Parvin Fallahi, Zahra Rezaeian, Sedighe Hoseinimosa,
Volume 15, Issue 2 (3-2017)

Background: There are different methods in endometrial preparation for frozen-thawed embryo transfer (FET).
Objective: The purpose of this study was to compare the live birth rate in the artificial FET protocol (estradiol/ progesterone with GnRH-agonist) with stimulated cycle FET protocol (letrozole plus HMG).
Materials and Methods: This randomized clinical trial included 100 women (18-42 years) randomly assigned to two groups based on Bernoulli distribution. Group I received GnRH agonist [Bucerelin, 500μg subcutaneously] from the previous midlutea lcycle, Then estradiol valerat [2 mg/ daily orally] was started on the second day and was increased until the observation of 8mm endometrial thickness. Finally progesterone [Cyclogest, 800 mg, vaginally] was started. Group II received letrozole on the second day of the cycle for five days, then HMG 75 IU was injected on the7PthP day. After observing [18 mm folliclhCG10000 IU was injected for ovulation induction. Trans cervical embryo transfer was performed in two groups. The main outcome was the live birth rate. The rate of live birth, implantation, chemical, and clinical pregnancy, abortion, cancellation and endometrial thickness were compared between two groups.
Results: Implantation rate was significantly higher in group I. Live birth rate was slightly increased in group I without significant difference (30% vs. 26%). The rate of chemical and clinical pregnancy was similar in two groups. The abortion rate was lower in letrozole protocol but the difference was not statistically significant. The mean endometrial thickness was not different between two groups.
Conclusion: Letrozole plus HMG method cannot improve pregnancy outcomes in frozen-thawed embryo transfer but it has only one injection compare to daily injections in artificial method
Marzieh Ghasemi, Masoumeh Kordi, Negar Asgharipour, Habibollah Esmaeili, Maliheh Amirian,
Volume 15, Issue 11 (11-2017)

Background: Waiting period of fertility treatment is stressful, therefore it is necessary to use effective coping strategies to cope with waiting period of intrauterine insemination (IUI) treatment.
Objective: The aim of this study was comparing the effect of the positive reappraisal coping intervention (PRCI) with the problem-solving skills training (PSS) on the coping strategies of IUI waiting period, in infertile women referred to Milad Infertility Center in Mashhad.
Materials and Methods: In this randomized clinical trial, 108 women were evaluated into three groups. The control group received the routine care, but in PRCI group, two training sessions were held and they were asked to review the coping thoughts cards and fill out the daily monitoring forms during the waiting period, and in PSS group problem-solving skill were taught during 3 sessions. The coping strategies were compared between three groups on the 10th day of IUI waiting period.
Results: Results showed that the mean score for problem-focused were significantly different between the control (28.54±9.70), PSS (33.71±9.31), and PRCI (30.74±10.96) (p=0.025) groups. There were significant differences between the PSS group and others groups, and mean emotion-focused were significantly different between the control (32.09±11.65), PSS (29.20±9.88), and PRCI (28.74±7.96) (p=0.036) groups. There were significant differences between the PRCI and the control group (p=0.047).
Conclusion: PSS was more effective to increase problem-focused coping strategies than PRCI, therefore it is recommended that this intervention should be used in infertility treatment centers.
Hüseyin Gurel, Nuri Baspinar, Pınar Peker Akalin, Vahdettin Altunok, Filiz Kazak,
Volume 16, Issue 6 (6-2018)

Background: Glucose-6-phosphate dehydrogenase (G6PD) is the first enzyme of the pentose phosphate metabolic pathway that supplies reducing agents by maintaining the level of reduced nicotinamide adenine dinucleotide phosphate.
Objective: It was aimed to determine the activity of erythrocyte and spermatozoa G6PD in the breeding and non-breeding seasons in Merino rams. And also, to find out the relation of these parameters with sperm quality parameters for better understanding the role of this enzyme in male fertility.
Materials and Methods: 1.5-2 yr-old healthy, 14 Merino rams were involved. Ejaculate samples were collected using an artificial vagina, in October (the breeding season) and April (the non-breeding season). Blood samples were collected prior to sperm collection. Sperm volume (ml), motility (%), mass activity (1-5), concentration (×106), viability (%), abnormal acrosome morphology (%) and abnormal sperm morphology (%) was evaluated. The activities of spermatozoa and erythrocyte G6PD were determined and the relation of sperm parameters with G6PD activity was evaluated.
Results: Erythrocyte G6PD activity was higher (p≤0.001), whereas spermatozoa G6PD activity was lower (p≤0.001) in the breeding season (1.928±0.231 U/g hemoglobin, 129.65±28.41 U/g protein, respectively) from that in the non-breeding (0.530±0.066 U/g hemoglobin, 562.36±94.92 U/g protein, respectively). There were also significant differences among sperm quality parameters within the seasons. Positive correlation was determined between spermatozoa G6PD activity (r=0.053, p=0.03 and sperm concentration in the breeding season.
Conclusion: Higher spermatozoa G6PD activity in October, where the level of polyunsaturated fatty acids is suggested to be increased, may reflect the increased need of nicotinamide adenine dinucleotide phosphate and thus higher G6PD activity for the oxidative balance.
Hassan Boskabadi, Ali Moradi, Maryam Zakerihamidi,
Volume 17, Issue 5 (5-2019)

1. Introduction
Perinatal asphyxia has been defined as the lack of oxygen that occurs either before, during, or after birth (1). It is a significant cause of perinatal morbidity and mortality as well as neurological disabilities in the surviving babies (2, 3). Annually, four million babies are born with perinatal asphyxia of whom, 800,000 die, and the same number experience adverse clinical outcomes (4). The mortality and morbidity rates among patients with moderate or severe Hypoxic Ischemic Encephalopathy (HIE) is very high. Half of patients with severe HIE will die, while almost all survivors suffer from neurodevelopmental deficits, cerebral palsy, epilepsy, and learning disorders (5, 6). A previous twoyr follow-up study has reported 26% mortality in asphyxic neonates, with 28% experiencing developmental delay (3). Several pathophysiologic mechanisms of brain damage in neonates are linked to HIE. Early assessment of the severity of a HIE-induced acute brain injury can be very useful for the prevention or treatment decisions in such neonates (7). The prediction of perinatal asphyxia is done using multiple assessments including the electronic monitoring of fetal heart rate during labor, cord or fetus pH measurements, meconiumstained amniotic fluid, Apgar score, the severity of HIE, prooxidant Antioxidant Balance (PAB), blood markers (Nucleated red blood cells (NRBC) in umbilical cord blood), and multiple organs impairments. None of these factors alone are sufficient and combinations of parameters are clinically used for early diagnosis of perinatal asphyxia (8, 9). Recent studies have focused on the inflammatory cytokines such as IL-1𝛽, IL6, and IL8 for early diagnosis of brain damage. As interleukins (ILs) are known as one of the early inflammatory responses to infections, they are potentially important in early diagnosis and hence proper management of both infectious and non-infectious conditions before the establishment of fulminant stage. The inflammatory cytokines are involved in the biochemical pathways leading to ischemic-hypoxic injury (10, 11). The role of inflammation in neonatal Central Nervous System (CNS) injuries as well as the role of cytokines as mediators of injuries have been identified (12). It is likely that the pathophysiology of perinatal asphyxia has a close relationship with the inflammatory mediators such as cytokines (13). Many of these cytokines such as IL-1𝛽, IL6, IL8, IL10, and IL12 increase during the inflammatory responses (14). A study has shown that cytokines cause brain damage through direct injury to the white matter, weakening the germinal matrix endothelium, brain hemorrhage, and inflammatory reactions caused by microglia and astrocytes (15). Although cytokines play a role in the regulation of cell apoptosis in CNS as well as leukocyte differentiation, proliferation, and infiltration, the precise role of pro-inflammatory cytokines such as IL6 as the main mediator in the development of brain damage is still unknown (16). Although several studies have been conducted on the relationship between the ILs and infectious conditions, however, comparison of their value in confirmation or rule out of the diagnosis of infection has not been fully discussed yet. Identification of biochemical markers such as IL may be useful for early diagnosis of asphyxia. Early diagnosis of perinatal asphyxia helps to provide better health care and improved outcomes. Brain injury is also a common cause of sever morbidity with poor outcomes and high mortality during the perinatal period. The current systematic review was conducted aiming at the identification of neonatal perinatal asphyxia by IL levels.
2. Materials and Methods
2.1. Selection of ILs for the diagnosis of neonatal asphyxia
After an initial review of the literature, a list of ILs was prepared to conduct a systematic review. The articles examining the role of ILs in the diagnosis of neonatal asphyxia were studied. In this regard, articles containing ILs such as IL-1, IL6, or combinations of both were analyzed for the diagnosis of neonatal asphyxia.
2.2. Search strategy
PubMed, Cochrane Library, Web of Science, Embase, and Scopus databases were used for this systematic review. “Asphyxia,” “neonatal asphyxia,” “perinatal asphyxia,” “interleukin,” and “diagnosis” were the search keywords. All articles in English and Persian between and consisting 1997 and 2016 were searched.
2.3. Inclusion criteria
Articles with the following criteria were selected for this review: (1) Neonates as the study population; (2) Neonatal asphyxia as the specified study; (3) ILs must be examined for the diagnosis or prediction of neonatal asphyxia in umbilical cord blood, serum, or Cerebro Spinal Fluid (CSF); and (4) Adequate information from the test results.
2.4. Exclusion criteria
Animal studies; articles that used other markers for the diagnosis of asphyxia rather than ILs; and articles with only abstract available were excluded from the study.
2.5. Data extraction and quality assessment of the articles
The full-text articles were downloaded and the extracted data were collected in Microsoft Excel with the following titles: the authors’ names and surnames, years of publication, methods, study areas, case groups, control groups, type of IL, locations of sampling, time for measuring IL, sensitivity, specificity; positive predictive value, negative predictive value, and the results of the investigation. Initially, 300 studies were collected using EndNote software and the duplicate articles (𝑛 = 115) were excluded from the review. According to the title and abstract, 65 more articles were excluded. A total of 107 other articles were also removed due to incomplete data, unavailability of full text, animal studies, uncertainty of the study type and the target group. Finally, 13 related articles underwent further analysis (Figure 1).  

Figure 1. Search strategy and selected articles.

3. Results
A total of 13 out of 300 articles with a total sample size of 1120 neonates were examined. Eight articles discussed IL6 (61.54%), two studies (15.38%) described about IL-1𝛽, and three articles (23.08%) were related to the combination of both ILs.
3.1. The number of the studies on ILs
The review of studies conducted from 1997 to 2016 showed that IL6 is the most frequently studied biomarker among IL family. Interleukins had been measured in 10 studies on serum samples (76.92%), 2 on CSF samples (15.39%), and 1 on umbilical cord blood samples (7.69%). All studies were prospective ones.
3.2. Heterogeneity of the articles
Studies on the relationship between IL and diagnosis of perinatal asphyxia were different in terms of inclusion criteria, sample size, sampling location, time of assessment, and the diagnostic value of ILs. Only five studies have discussed the diagnostic value of IL (38.46%). The cutoff values for both IL6 and IL-1𝛽 were 11.91-100, and negative predictive values of ILs were different in the articles under study (Figure 2, Table I). 

Figure 2. The sensitivity, specificity, positive, and negative predictive values (%) of IL6 in prediction of asphyxia∗. and its adverse outcomes† .
3.3. IL6 (eight studies)

In a study on serum levels of IL6 at birth, 24 and 48 hr after delivery for 37 neonates with perinatal asphyxia and 45 healthy neonates serum concentrations of IL6 was reported as 43 times higher in asphyxiated neonates with HIE and 1.9 times higher in asphyxiated neonates without HIE compared to the healthy neonates. Serum concentrations of IL6 were increased in neonates with asphyxia after birth and this was associated with the severity of encephalopathy and poor outcomes. The sensitivity, specificity, positive, and negative predictive value of IL6 in prediction of asphyxia and its adverse outcomes are shown in Figure 1. So following cerebrospinal system injury, IL6 plays an important role and its serum concentrations can be a useful predictor of HIE outcomes (1). Another study comparing the IL6 in 50 neonates with non-infectious perinatal asphyxia with 113 healthy neonates at similar time points showed that the average concentrations of IL6 in neonates with HIE were 376 times higher than the healthy babies and 5.5 times higher in neonates with asphyxia without HIE. A critical relationship was also found between IL6 and the degree of HIE as well as neuro-developmental outcomes at two yr. Regardless of the outcomes, serum IL6 concentration was significantly lower in the first 24 and 48 hr after birth. Umbilical cord concentration of IL6 > 100 pg/ml had the sensitivity and specificity of 70.8% and 80.9%, respectively, in predicting moderate to severe HIE. It was concluded that IL6 measurement in the umbilical cord blood of newborns with perinatal asphyxia may be useful in early detection of neonates with high risk of brain damage and adverse outcomes (17). A study on the neurological markers (IL6) in perinatal asphyxia and its relationship with different stages of HIE was performed on 100 asphyxic and 100 healthy neonates with blood samplings in the first and third days of birth. The results showed that the average concentration of serum IL6 on the third day of birth of asphyxic neonates declined. There was also a negative relationship between IL6 concentrations in the first and third days of birth. The IL6 concentration had a reverse correlation with the HIE stages (Stages 1-3) within the 1st to the 3rd day of birth. In addition, there was a negative relationship between the first and third day of life in terms of IL6 concentrations in various stages of HIE. It was concluded that IL6 concentration increases after birth asphyxia, and this increase is associated with the severity of HIE and poor outcomes (18). In a study on the predictors of early HIE in Egypt, serum IL6 was measured in the first 12 hr of life in 27 perinatal asphyxic as well as 25 healthy neonates. The HIE group showed significantly higher IL6 levels compared to the controls. IL6 measurements have also been performed in the CSF of full-term neonates with HIE. This prospective study was performed on 20 healthy newborns (no sepsis or meningitis; 1 and 2 min Apgar scores ≥ 9) and 15 neonates in the case group (with asphyxia and Apgar score of ≤ 4 in the first minute and ≤ 6 in the fifth minute, umbilical cord blood pH < 7.20 or lactate > 3 mmol/liter in the umbilical artery blood and need for artificial ventilation for at least two minutes after birth). The CSF samples were collected within the first 48 hr after birth to identify IL6. The results showed that the average IL6 in the case group (157.5 pg/ml) was significantly higher than the control group (4.1 pg/ml). The researchers concluded that IL6 levels in term neonates with HIE is higher than the control group (19). A different study aiming at the evaluation of IL6 in CSF after perinatal asphyxia and its relationship with early and late nervous observations was conducted on 20 infants, among whom, 3 cases had no HIE (stage 0), 5 infants were at stage 1, 6 infants at stage 2, and 6 infants at stage 3 of HIE. The IL6 concentration in CSF (from 8 to 90 hr of birth) in infants at stage 3 of HIE was higher than those at stage 0 to 2. Infants with brain damage and adverse outcomes showed higher CSF levels of IL6. The increase in CSF IL6 after perinatal asphyxia was related to the intensity of HIE, brain damage, and neurological outcomes. The researchers concluded that IL6 may be involved in hypoxic-ischemic brain damage (20). A study on the clinical significance of serum IL6 in neonates with HIE was performed on 74 neonates with HIE along with 74 healthy neonates. An increase in the inflammatory mediators was associated with the severity of the disease and positively correlated with prognosis. They reported high levels of IL6 in neonates with HIE. High concentrations of IL6 in infants with HIE suggests that these inflammatory mediators play an important role in the development and prognosis of the disease (21). Serum concentrations of 50 asphyxic and 20 healthy neonates were measured on days 1, 3, and 7 after birth in a study on the relationship between IL6 and brain damage in perinatal asphyxia. The results showed that IL6 levels in asphyxic neonates reduced within a week after birth and reverted to the normal level on day 7 after birth; however, the IL6 levels were significantly lower in neonates with brain damage compared with neonates with no brain injury. As a conclusion, IL6 levels increase in neonatal asphyxia; hence, it can be involved in the pathophysiology of neonatal asphyxia (22). 
3.4. IL-1𝛽 (two articles)
Serum levels of IL-1𝛽 were studied in 38 neonates with non-infectious perinatal asphyxia (blood pH < 7.2, low Apgar score, and fetal distress symptoms) and 41 healthy neonates (natural babies with no clinical signs of asphyxia during the first week after delivery) at birth as well as 24 and 48 hr after the delivery. The serum levels of IL1𝛽 in neonates with HIE were five times more than asphyxiated newborns without HIE and six times higher than healthy babies. Also, a significant relationship was found between IL-1𝛽 and neonatal outcomes at discharge. The sensitivity, specificity, positive, and negative predictive value of IL-1𝛽 in prediction of the occurrence of asphyxia and its adverse outcomes are shown in Figure 3.

Table I. Summary of the studies conducted on the diagnosis of perinatal asphyxia by assessing interleukins (ILs)

Table I. Continued

Figure 3. The sensitivity, specificity, positive, and negative predictive values (%) of IL-1𝛽 in the prediction of the occurrence of asphyxia∗. and its adverse outcomes† .

The researchers concluded that the increase in serum levels of IL-1𝛽 in asphyxic neonates is a predictor of poor outcomes. In other words, serum IL-1𝛽 is a predictor for the severity of perinatal asphyxia and its short-term neural outcomes (23). A different prospective study was conducted on the predictive value of plasma and CSF concentrations of IL-1𝛽 in the outcomes of 30 term neonates with HIE. Blood and CSF samples were collected within the first 24 hr after birth. Five babies died immediately after hypoxia. The neurological examination and Denver Developmental Screening Test were performed at one yr of age. Eleven neonates had normal and fourteen had abnormal neurological findings or abnormal Denver Developmental Screening Test. The results indicated that the CSF concentration of IL-1𝛽 in unhealthy infants was significantly higher than healthy ones. However, no significant difference was found in the plasma concentrations of IL1𝛽 in two groups. Patients with CSF samples taken within six hr of hypoxia had higher levels of IL-1𝛽 compared to those with sampling after six hr of hypoxia. The researchers concluded that IL-1𝛽 level is correlated with CNS damage after hypoxia and can be a useful predictor for HIE (24).
3.5. Combination of IL6 and IL-1𝛽 (three articles)
Combination of IL6 and IL-1𝛽 at birth was studied in 38 infectious infants with perinatal asphyxia (pH < 7.2, low Apgar score, and fetal distress symptoms) and 47 healthy infants. Serum concentrations of IL6 and IL-1𝛽 were significantly higher in infants with perinatal asphyxia compared to the healthy ones (88.15 vs. 6.74pb/ml for IL6 and 16.88 vs. 3.34pb/ml for IL-1𝛽). The sensitivity and specificity of IL6 and IL-1𝛽 are shown in Figure 4. The turning points for IL6 and IL-1𝛽 were 11.91 pb/ml and 3.35 pb/ml, respectively. The researchers concluded that simultaneous assessment of IL6 and IL-1𝛽 can improve the sensitivity and specificity for early diagnosis of perinatal asphyxia. In addition, the assessment of the combination of IL-1𝛽 and IL6 was the best indicator for perinatal asphyxia (25). 

Figure 4. The sensitivity and specificity (%) of IL6 and IL-1𝛽 in prediction of diagnosis of perinatal asphyxia.

In a different study on evaluation of the markers for early diagnosis of brain damage in the preterm low-birth-weight infants with perinatal asphyxia, 29 infants with perinatal asphyxia and 28 healthy infants were involved. Serum IL6 and IL-1𝛽 were measured in the first 24 hr and the 3rd and 7th days of birth. The study results showedthat serum IL6 and IL-1𝛽 were significantly higher in infants with perinatal asphyxia in the first 24 hr after birth compared to the healthy infants. Neurologic evaluation of 14 infants with perinatal asphyxia and 12 healthy ones at 18 months of age revealed that 8 infants with perinatal asphyxia had abnormal findings that were associated with serum levels of IL6 and IL-1𝛽 in 24 hr after birth. The researchers concluded that increased levels of proinflammatory cytokines are the primary findings for the future neurological disorders in infants with asphyxia (26). In an evaluation of the inflammatory cytokines in 55 healthy and 45 infants with HIE, serum levels of IL6 and IL-1𝛽 were measured at birth, 24, and 72 hr after birth. A significant increase was found in IL6 and IL-1𝛽 in infants with HIE at three time points (27). The combination of IL6 and IL-1𝛽 had the highest average sensitivity (92.9%) and specificity (85.43%) among diagnostic ILs in asphyxiated infants (Table II).

Table II. Average diagnostic value of interleukins (IL) in relation to infant asphyxia

4. Discussion
Perinatal asphyxia is a common and serious problem that results in annually almost a million infant deaths in the world. Perinatal asphyxia may also have negative impacts on all main body organs (3). HIE increases the quick expression of inflammatory cytokines of brain (IL1 and IL6) (28). IL6 level is one of the powerful predictors of HIE outcomes such as death and long-term neuro-developmental problems (17). It appears as a considerable product among inflammatory cytokines in the pathogenesis of perinatal asphyxia (29). IL6 is as an inflammatory mediator in brain injury and plays a central role in the inflammatory responses (30). It is not clear whether IL6 has a devastating effect on neurons or healing effect after brain ischemic damage (31). IL6 may be released as a protective response after hypoxic-ischemic brain damages. It acts as a cytokine with two pro-inflammatory and antiinflammatory properties (32). IL6 has been shown to play two roles in cerebral ischemia: as an inflammatory mediator during the acute phase and as a neurotrophic mediator within the acute and long-term stages (33). Higher levels of IL6 have been reported in infants with perinatal asphyxia and hypothermia (34). IL6 is involved in the induction of acute reactions and control the inflammatory responses causing a reduction in pro-inflammatory cytokines and an increase in anti-inflammatory molecules during acute cerebral ischemia stage (35). IL6 increases in CSF fluid in asphyxic infants and is related with the severity of HIE (20). A direct relationship has been reported between the CSF levels of IL6 and TNF-𝛼 and neurological prognosis after acute cerebral ischemia in adults (36). It has been shown that CSF levels of IL6 are significantly higher in infants with severe neurological observations compared to mild or moderate encephalopathy (20). Increased IL6 in the CSF has been shown to be related with the severity of HIE, brain injury, and neurological outcomes at 12 or 72 hr after perinatal asphyxia (20). Serum concentrations of IL6 increased approximately 12 hr after birth (1). A recent study reported an increase in serum levels of IL6 in infants with HIE (32). Animalstudies have shown an increase in the peak serum levels of IL6 in rats with HIE in 6 hr after creating HIE so that the concentration of IL returns to the base level after 20 hr (28); however, researchers have not specified a certain turning point for IL6 that predicts long-term adverse outcomes. A significant relationship has been reported between the serum concentrations of IL6 and Sarnat encephalopathy grading (31). Also, increased levels of IL6, IL11, and IL13 have been reported in dried blood samples of infants with cerebral palsy (37). The results of an animal study showed that the serial injection of synthetic IL6 prevents learning disabilities and delays the loss of neurons (38). In another study, the increase in serum IL6 was associated with poor outcomes or death in infants with perinatal asphyxia (39). An increased IL6 in amniotic fluid and cord blood were associated with outcomes such as cerebral palsy and periventricular leukomalacia, respectively (40). Cohort Study of Ahearne and co-worker is the first report that measured the association of IL-16 in neonates with perinatal asphyxia at birth and long-term outcome. IL16 is an early biomarker of severe injury that determine the long-term prognosis of infants with HIE. 
Serum IL6 had 86% positive predictive value and 100% specificity in predicting moderate to severe HIE (41). Available studies have indicated that IL6> 41 pg/dL had sensitivity and specificity of 88.84% and 85.43%, respectively, in the diagnosis of neonatal asphyxia. Therefore, the highest sensitivity and specificity are for the diagnosis of asphyxia related to IL6. IL-1𝛽 in umbilical cord is a major bio-outcome for brain injury whose levels are significantly high in infants with HIE and predict severe HIE and adverse outcomes in 6 to 12 months of age (42)
Increased CSF concentrations of IL-1𝛽 are associated with neurologic outcomes after perinatal asphyxia. It could be concluded that IL-1𝛽 has neurotrophic and neuroprotective results. However, it is not clear whether IL-1𝛽 is involved in the destruction or repair of neurons after ischemic brain injuries (31). CSF levels of TNF-𝛼 and IL-1𝛽 were higher in term infants with HIE who developed nervous disorders in one age (43). Neuroprotective antagonist effects of IL-1𝛽 receptor against brain damages before or after exposure to hypoxia have already been reported (44). The available studies showed that IL-1𝛽> 4.7 pg/dl had sensitivity and specificity of 78% and 83%, respectively, in the diagnosis of neonatal asphyxia. IL-1𝛽 and IL6 are significantly increased in birth asphyxia and the rate of increase is associated with the severity of encephalopathy. Simultaneous assessment of IL-1𝛽 and IL6 is the best indicator of perinatal asphyxia (25). IL-1𝛽 and IL6 levels have been reported to be significantly higher in infants with perinatal asphyxia compared to the control group in 24 hr after birth (26). In another study, serum levels of IL6, IL8, and IL10 were higher in infants with severe asphyxia (death or poor outcome) than those with asphyxia but no poor outcome (39). Serum concentrations of IL-1𝛽 and IL6 were significantly higher in infants with perinatal asphyxia than that in healthy infants. Simultaneous assessment of IL1𝛽 and IL6 improved the sensitivity and specificity of early diagnosis of perinatal asphyxia. Assessment of combined IL-1𝛽 and IL6 was suggested as the best indicator of perinatal asphyxia (25). Available studies indicated that simultaneous assessment of IL-1𝛽 and IL6 had the sensitivity of 93% and specificity of 43.5% in the diagnosis of neonatal asphyxia. The current review is the only study that has examined the role of IL in the diagnosis of perinatal asphyxia. Limitations of this study include the lack of access to unpublished articles and reports, inappropriate and low-quality reports, limited number of articles and infeasibility of accurate judgments about their effectiveness, lack of similar definitions for case groups, lack of cutoff point calculations, and lack of diagnostic value of IL in all the studies under review.

5. Conclusion
Serum and CSF concentrations of interleukins IL6 and IL-1𝛽 increased after asphyxia and the rate of increase was associated with the severity of asphyxia and adverse outcomes. Therefore, combination of IL6 and IL-1𝛽 can be used as a potential substantially powerful marker for early diagnosis of perinatal asphyxia. Further studies are required in order to identify more involved ILs and standardize their cutoff values in early diagnosis of neonatal asphyxia.

Conflict of Interest
The authors declare no conflict of interest.
Tetsuji Minami, Hayato Yamana, Daisuke Shigemi, Hiroki Matsui, Kiyohide Fushimi, Hideo Yasunaga1,
Volume 17, Issue 10 (10-2019)

Background: The optimal colloid solution for the treatment of ovarian hyperstimulation syndrome (OHSS) remains to be established.
Objective: We aimed to compare artificial colloids (AC) with human albumin (HA) for the treatment of OHSS.
Materials and Methods: In this retrospective cohort study, data for OHSS participants were collected from a national inpatient database in Japan. The participants received intravenous fluid management with AC (n = 156) or HA (n = 127). We compared the two groups in terms of the length of stay, development of post-treatment complications, and termination surgery.
Results: In multivariable linear regression analyses for log-transformed length of stay with reference to the OHSS participants receiving AC, the regression coefficient (95% confidence interval) in participants receiving HA was 0.03 (-0.04-0.09, p = 0.42). Thromboembolism occurred in two participants in the HA group and three participants in the AC group. Two participants in the HA group suffered renal failure during hospitalization. No participants underwent termination surgery in the two groups.
Conclusions: The present results showed comparable efficacy between AC and HA for the treatment of OHSS. There were no significant differences in post-treatment complications between the two groups.
Alamtaj Samsami, Leila Ghasempour, Sara Davoodi, Shaghayegh Moradi Alamdarloo, Jamshid Rahmati, Ali Karimian, Hamide Homayoon,
Volume 17, Issue 12 (12-2019)

Background: The endometrial preparation with stimulating natural cycles for frozen embryo transfer (FET) have benefits like lower cost and ease of use.
Objective: Comparing the clinical outcome of letrozole versus hormone replacement (HR) for endometrial preparation in women with normal menstrual cycles for FET in artificial reproduction techniques.
Materials and Methods: A total of 167 participants who had frozen embryos and regular ovulatory cycles were randomly divided into two groups for endometrial preparation. One group (82 women) was stimulated with letrozole 5mg/day and the other group (85 women) was hormonally stimulated by oral estradiol valerate (2 mg three times a day). All participants were followed serially by ultrasonography. Any patient who did not reach optimal endometrial thickness was excluded from the study. Implantation, biochemical and clinical pregnancy and abortion rate were reported.
Results: There was no significant difference in the mean age, duration, and primary or secondary infertility, cause of the infertility, number, and quality of transferred embryos between the groups. The mean estradiol level on the day of transfer was 643 ± 217 in the HR group and 547 ± 212 in the letrozole group (P = 0.01), which was significantly different. The clinical pregnancy rate was 38.7 in the letrozole group, higher than the HR group (25.3) but not significantly different (P=0.06).
Conclusion: For endometrial preparation in women with a normal cycle, letrozole yields higher pregnancy rate although it is not significant; due to its cost, ease in use, and lower side effects, letrozole is a good choice.

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