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Thursday, November 21, 2019

Recent advances in in vitro fertilization







Abstract

The field of assisted reproductive technology is rapidly progressing with many new advances in the last decade. The present review discusses methods to improve oocyte quality in older women and new stimulation protocols that may improve the number of mature oocytes retrieved during an in vitro fertilization cycle. We will discuss the present use of pre-implantation genetic screening (PGS) and finally focus on some new methods to determine endometrial receptivity. The focus of this review is to point out areas of technology that may be controversial or are new enough to require proper controlled studies for validation.

Keywords: IVF, Co-enzyme Q10, Letrozole, PGS

Introduction

In this review, we were asked to update the readers of F1000 on the rapidly advancing field of assisted reproduction. There have been too many new technologies that have been developed over the last 5 years to cover in detail in this review, so we decided to focus on advances that have generated some controversy or that are new enough to require further validation in the future. We plan to discuss methods to improve oocyte quality, especially in older women, together with new stimulation protocols that may improve the number of mature oocytes retrieved during an in vitro fertilization (IVF) cycle. We will discuss the present controversy around pre-implantation genetic screening (PGS) and finally focus on some controversial new methods to determine endometrial receptivity. Needless to say, much of what we have to say in this review will reflect our personal opinions in some of these areas.

Improving oocyte quality: the role of mitochondria

The reproductive capacity of women decreases significantly in the fourth decade, which is directly correlated to an age-related decrease in oocyte quality and quantity . Fecundity starts decreasing gradually at age 32 and then drops exponentially after 38 . The fact that live-birth rates from oocyte donation in older women are consistent with the age of the donor suggests that oocyte quality is the major factor responsible for reduced fecundability with aging. The pathways leading to increased loss of ovarian follicles in “old” ovaries are not fully understood, although increased DNA damage due to a less active DNA repair mechanism is a possible trigger for oocyte loss . The decreased quality of oocytes involves an increased rate of chromosomal aneuploidy with aging predominantly related to meiotic errors during oocyte maturation. The oocyte maturation process involves a combination of nuclear, cytoplasmic, and epigenetic changes, all of which require energy that is provided by the mitochondria via oxidative phosphorylation (OXPHOS) .

Co-enzyme Q10 supplementation

The production of ATP via OXPHOS involves a complicated process including  complexes located on the inner mitochondrial membrane 1. Ubiquinone or coenzyme Q10 (CoQ10) plays an important role in this process, as it has antioxidant properties, controls cellular redox, and affects various signaling pathways. The concentration of CoQ10 in most tissues decreases after 30 years of age in humans and this decline in CoQ10 may contribute to the aging process, since it coincides with the decline in fertility and increased rate of aneuploidies. Ben Meir et al. in 2015 showed that supplementation of CoQ10 in an aged animal model delayed decline in ovarian reserve, restored oocyte mitochondrial gene expression, and improved mitochondrial activity with a significant reduction in oocyte aneuploidy. As a result, these aged mice had more oocytes with stimulation, the developmental potential of the oocytes was improved, and more offspring were born compared to old animals receiving placebo 1. As a follow-up study, conditional disruption of the gene PDSS-2, resulting in isolated CoQ deficiency in the oocytes of young animals, resulted in phenotypic changes characteristic of oocyte mitochondrial dysfunction associated with aging. By feeding the animals CoQ10, these changes could be reversed.

Since CoQ10 administration in old animals was shown to have beneficial effects on reproductive outcomes, one could speculate that older women might have the same benefits when supplemented with CoQ10 . At present, there is much research activity in this area. Although the animal model appears promising, the aging process differs greatly between mice and women because of the huge difference in lifespan. CoQ10 administration for 12–16 weeks in mice is likely equivalent to years of use in humans and thus additional large-scale clinical studies are needed.

Mitochondrial transfer

Other attempts to overcome ooplasmic aging have utilized oocyte manipulation at a subcellular level. Cohen et al. performed ooplasmic transfer from donor oocytes into mature oocytes of patients who had failed multiple IVF cycles because of poor embryo development and showed healthy live births as a result . Since cytoplasm contains mitochondria, mitochondria from the donor ooplasm were also transferred into the recipient eggs and were believed to be the most important mediator of improved embryogenesis. Several of the healthy babies tested were found to be heteroplasmic, i.e. to have mitochondrial DNA (mtDNA) derived from the mother and the cytoplasm donor and the procedure of ooplasm donation is no longer used. However, autologous mitochondrial transfer has now extended this previous work with ooplasm transfer. In this new technology, mitochondria similar to oocyte mitochondria are isolated from oocyte precursor cells in the superficial epithelial layer of the patient’s ovary and are injected into the patient’s own oocytes at the time of fertilization. This mitochondrial injection has been demonstrated to improve embryo development and lead to live births in women with previous poor embryo development. This technique, and even the presence of oocyte precursor cells, remains controversial and needs proper randomized control studies for validation.

Improving oocyte quality with new stimulation and triggering protocols

Co-treatment with gonadotropins and letrozole in in vitro fertilization

Recently, a few studies have demonstrated a potential benefit of the use of the oral agent letrozole together with gonadotropin stimulation in IVF cycles, especially in breast cancer patients going through fertility preservation treatment. The goal of co-administration of letrozole is to reduce serum estrogen concentrations during ovarian stimulation in breast cancer patients. These studies showed that treatment of breast cancer patients with letrozole and gonadotropins throughout the entire stimulation significantly decreased estradiol concentrations as expected but, interestingly, also increased the number of mature oocytes for cryopreservation compared to controls without breast cancer treated with standard COH. As far as we know, only breast cancer patients undergoing IVF treatment have been treated with letrozole during the whole stimulation phase so far. In our opinion, however, this protocol is likely an excellent treatment for normal responders undergoing IVF to lower the dose of gonadotropins required to obtain adequate numbers of oocytes for fertilization and to keep estrogen levels closer to the physiologic range.

There are some limited data for the use of letrozole in IVF cycles of normal responders involving co-administration of gonadotropins and letrozole for 5 days in the early follicular phase. Favorable outcomes related to letrozole were reported, including lower doses of gonadotropin, which decreased the cost of the IVF treatment, and increased numbers of oocytes and mature oocytes while achieving the same pregnancy rate compared to conventional stimulation. More data exist for the use of letrozole in IVF cycles of poor responders. The rationale for co-treatment with letrozole in poor responders is to increase the intrafollicular androgen concentrations, which have been shown to serve as precursors for ovarian estrogen synthesis as well as having a fundamental role in ovarian follicular development by augmentation of FSH receptor expression on granulosa cells . Co-administration of letrozole and gonadotropins has been described to improve the outcomes in poor responders undergoing IVF cycles. Garcia-Velasco et al. in 2005 evaluated the impact of letrozole as an adjuvant treatment in IVF cycles on intraovarian androgens and cycle outcome. They found that adding 2.5 mg of letrozole for the first 5 days of gonadotropin stimulation significantly increased follicular fluid androstenedione and testosterone concentrations and improved IVF cycle outcome. They found a significantly larger number of retrieved oocytes and a significantly higher implantation rate in the letrozole group compared to the control group.

Although the results of these studies are promising, further prospective studies will be needed to confirm the potential benefit of adding letrozole to gonadotropins in both normal and poor responder patients undergoing IVF.

Pre-treatment with dehydroepiandrosterone/testosterone

Considering the profound effect intraovarian androgens may have on early follicular growth, different protocols have been used to try to increase intrafollicular androgen concentrations in poor responder patients.

Pre-treatment with transdermal testosterone was shown to improve ovarian sensitivity to FSH and follicular response to gonadotrophin treatment in low-responder IVF patients and resulted in an increase in the number of cumulus oocyte complexes retrieved as well as improved clinical pregnancy and live-birth rates.

Gleicher et al.  investigated patients with diminished ovarian reserve who were supplemented with dehydroepiandrosterone (DHEA) for 30–120 days (25 mg 3 times daily). They demonstrated higher AMH levels in the treated patients compared to the non-treated patients, and they also demonstrated improved pregnancy rates. The same group also demonstrated that DHEA may reduce embryo aneuploidy rate and also miscarriage rate . Wiser et al. performed a prospective randomized controlled study of the effect of DHEA supplementation on IVF outcomes among poor-responder patients. He found an improvement in the embryo quality and a significantly higher live-birth rate in the DHEA group compared with controls. The number of eggs and zygotes was similar in both groups. The use of DHEA for older women or poor responders remains controversial because of the paucity of randomized controlled trials.

New data regarding a double trigger for in vitro fertilization

In most mammalian species, spontaneous ovulation is preceded by a surge of both FSH and LH, which is thought to be necessary for final oocyte maturation and initiation of follicular rupture. At present, standard IVF cycles utilize hCG as a surrogate for the LH surge. In contrast to hCG, the GnRH agonist-induced gonadotropin surge mimics the natural mid-cycle surge and exposes follicles to both LH and FSH.

Although previous studies suggested that more mature oocytes may be retrieved with GnRH agonist for ovulation triggering compared to hCG, the GnRH agonist trigger resulted in luteal phase insufficiency caused by lysis of the corpus luteum and poor pregnancy rates.

Griffin et al. showed that a combination of hCG and GnRH agonist (double trigger) in women with more than 25% immature oocytes in previous IVF cycles resulted in a significant increase (2 and a half times higher) in the proportion of mature oocytes retrieved. Similarly, Zilberberg et al. found a significantly higher number of mature oocytes, embryos, and top-quality embryos in a similar group of women using the double trigger instead of hCG alone.

Lin et al. investigated whether the double trigger could improve the live-birth rate in normal responders undergoing a GnRH-antagonist protocol for IVF compared with hCG alone as the trigger. In their retrospective cohort study of almost 400 cycles, the mean number of MII oocytes retrieved was significantly greater in the dual-trigger group, as was the implantation, clinical pregnancy, and live-birth rates, when compared to the hCG trigger group. All of these studies, albeit retrospective, suggest an advantage to using a GnRH agonist with hCG as a double trigger in IVF cycles, and future prospective studies are needed to confirm.

Time-lapse imaging
Elective single embryo transfer has been suggested as the most efficient approach to minimize multiple pregnancies resulting from assisted reproduction treatments, and the traditional morphological evaluation has remained the first-line method for selecting the most developmentally competent embryo from an available cohort.

During the last decade, time-lapse imaging (TLI) has emerged as a novel technology that enables continuous evaluation of early embryo development by automated image acquisition every 5–20 minutes and accordingly does not rely on static observations to define a highly dynamic process. Furthermore, it is possible to score embryos without removing them from the incubator, so there is no exposure to changes in light, humidity, temperature, pH, or gas.

Many morphokinetic parameters have been identified to correlate with the embryo's ability to create a pregnancy, and many different embryo-selection algorithms have been proposed to increase the prediction rate. Recently, Barrie et al. performed a retrospective observational analysis that demonstrated a need for the development of in-house embryo-selection algorithms that are specific to the patient, treatment, and environment. Their data suggested that currently available algorithms are not clinically applicable and lose their diagnostic value when externally applied.

A recent meta-analysis assessed whether TLI resulted in favorable outcomes for embryo incubation and selection compared with conventional methods in clinical IVF. This analysis included 10 randomized controlled studies and concluded that there is insufficient evidence to support TLI as a superior method compared to conventional methods for human embryo incubation and selection. A well-designed RCT is still needed to evaluate the effectiveness of the clinical use of TLI.

Pre-implantation genetic screening for aneuploidy

The objectives of PGS for aneuploidy are to select embryos with the highest chance of implantation, to facilitate elective single embryo transfer, and to reduce the risk of chromosomal abnormalities in the offspring. The current embryo biopsy technique for PGS, day 5 multi-cell trophectoderm biopsy, has replaced the old day-3 single blastomere biopsy and is thought to have a much-improved embryo implantation rate. The genetic testing methods for PGS have also achieved higher accuracy with the progression of test platforms from FISH, to aCGH, SNP arrays, Q-PCR, and the current next-generation sequencing (NGS) technology . PGS may demonstrate abnormal results in more than three-quarters of embryos tested. However, recent research showed that some of these diagnosed abnormal embryos may have the potential to develop into healthy babies. Embryo mosaicism and the trophectoderm sampling technique presently utilized are two major reasons for the possible inaccuracy of PGS.

Embryo mosaicism is an extremely controversial topic at the moment. Mosaicism of the chromosomal complement in an embryo can be observed at different stages of embryonic development and is thought to arise during mitotic cell divisions after fertilization. Mosaic cells might reside within the inner cell mass, in the trophectoderm, or in both. Also, the distribution of mosaic cells in the blastocyst can be local, patchy, or uniform. Animal studies found a wide range of mosaic embryos. A recent study using discarded human embryos found similar wide ranges of embryo mosaicism, ranging from 20 to 90% of embryos . Until now, there is not enough clinical data to predict the fate of the embryos with mosaicism, and there is a clinical and ethical debate around whether embryos determined to be chromosomally mosaic could, or should, be transferred.

Animal studies have shown that some mosaic embryos can implant and develop into healthy babies through self-correction. A few clinical reports so far have demonstrated normal pregnancies after transferring abnormal PGS embryos. Lledo et al. used aCGH to re-evaluate trophectoderm biopsy samples and found that 13.4% of embryos previously diagnosed as euploid were mosaic . The clinical pregnancy rate was thought to be similar between mosaic and euploid embryo transfers, but the miscarriage rate may be higher in the mosaics. Fragouli, using NGS to analyze trophectoderm biopsies, found a lower pregnancy rate in mosaic embryos compared to euploids. Both studies, however, provided evidence that embryos with certain degrees of mosaicism may develop into healthy babies.

Another controversy concerns the accuracy of PGS as it is now practiced. A recent computer modeling study showed that a single trophectoderm biopsy of 5 to 6 cells cannot accurately estimate the degree of embryo mosaicism, casting into doubt the entire value of PGS. Possible ways to solve this problem include multiple trophectoderm biopsies or, better yet, biopsy of the inner cell mass. However, the safety of removing cells from the inner cell mass is not yet established.

Assuming an accurate method of detecting mosaic embryos, an ethical controversy is whether the transfer of these embryos would carry a high risk of miscarriage. On the other hand, discarding aneuploid and mosaic embryos using our present biopsy techniques could potentially result in the loss of embryos that have the potential to develop into a normal baby. This area of controversy will not be solved in the near future.

mtDNA content in blastocysts

An offshoot of PGS and trophectoderm biopsy is the ability to determine the mean mtDNA copy number in the blastocyst. Elevated mtDNA copies at the blastocyst stage have been found to be associated with poorer clinical outcome . Euploid embryos with relatively low levels of mtDNA at the blastocyst stage were observed to have a higher implantation rate compared to blastocysts with a relatively higher copy number of mtDNA. In keeping with the latter observation, blastocysts from younger patients have been found to have lower average copy numbers of mtDNA compared to older patients. This difference was evident when all blastocysts were considered together but also when chromosomally normal and abnormal embryos were considered separately. This finding raises the question of whether mitochondria might play a direct role in the decline of female fertility with age. Fragouli et al. examined mtDNA quantity in relation to chromosome status. They found that chromosomally abnormal blastocysts tended to contain significantly larger amounts of mtDNA compared to those which were characterized as being euploid. The elevated mtDNA levels in the abnormal and the older embryos might be a consequence of a compensatory mechanism aimed to increase the ATP generation of compromised mitochondria of reduced function. At present, the analysis of mtDNA copy number at the blastocyst stage as a way to improve live-birth rates is controversial, and further research is ongoing.

New approaches to assess the receptivity of the endometrium

Embryo implantation occurs following complex synchronized physiological and biochemical interactions between the blastocyst and the endometrium . This occurs only if the endometrium is in a receptive state. In humans, an individually defined period called the “window of implantation” (WOI) spans 2–4 days during the mid-luteal phase . Two recent methods used in IVF clinics for the assessment of endometrial receptivity are ultrasound measurement of subendometrial wave frequency and a microarray analysis of putative implantation-associated gene expression, the so-called endometrial receptivity array (ERA).

Ultrasound assessment of endometrial receptivity
Early studies using transvaginal ultrasound (TVUS) measurement of endometrial thickness hoped to replace invasive techniques like endometrial biopsy for the assessment of endometrial receptivity. A pre-ovulatory endometrium of 7 mm is considered as the cut-off thickness below which suboptimal implantation occurs . However, pregnancies have been reported in patients with an endometrial thickness as low as 4 mm . A meta-analysis in 2014 concluded that endometrial thickness by itself did not have a high enough positive predictive value for pregnancy .

More recent work has focused on TVUS measurement of the subendometrial contractility, observed as “endometrial waves”, that are hormonally responsive in their patterns and propagation directions. In the follicular phase, these peristaltic waves are directed from the fundus to the cervix (FC waves), but in the late follicular and the ovulatory phase these waves are directed from the cervix to the fundus (CF waves) to assist sperm transportation to the fallopian tube. Following ovulation is a phase of uterine quiescence which would support embryo implantation . During assisted reproductive technology procedures, supraphysiological estradiol levels are generally reflected by increased wave activity. Fanchin et al. observed an inverse correlation between the frequency of subendometrial waves in the luteal phase and pregnancy outcomes . Increasing progesterone exposure was shown to result in diminished wave activity and improved pregnancy rates. Despite these interesting observations, most IVF units at present do not use ultrasound to assess endometrial wave activity. However, in our opinion, this non-invasive tool could be especially valuable in patients with recurrent implantation failure or with inflammatory conditions such as endometriosis to ensure uterine quiescence prior to the embryo transfer.

Molecular test of endometrial receptivity
Endometrial histological dating described by Noyes et al. in 1950  was considered the gold standard for determining the WOI, thought to be around day 20 to 22 of an idealized 28-day cycle. Endometrial deficiency or “out-of-phase” endometrium is thought to occur in as many as 1 in 4 patients . Multiple randomized studies have cast doubt on the reproducibility of the analysis of endometrial biopsy samples by histologic dating. A new technique has developed from the transition to microarray molecular analysis using a customized array to identify markers of endometrial receptivity. The ERA based on the analysis of the expression of 238 genes thought to be involved in endometrial implantation may lead to the determination of the personalized WOI. This test is done by obtaining endometrial biopsy samples on day LH surge + 7 in a natural cycle or the 6 th day of progesterone

administration during an HRT cycle. Results are expressed as pre-receptive, receptive, or post-receptive. If the result is non-receptive, which happens in 1 in 4 patients, the embryo replacement timing is adjusted, enabling personalized embryo transfer. This technique, although offered commercially, still requires large-scale randomized studies for validation and the results remain controversial.


Friday, June 28, 2019

Clinical Trial begins for male contraceptive gel that can be rubbed onto chest, shoulder




A contraceptive gel made up of synthetic versions of the sex hormones progesterone and testosterone is being tested as an alternative to a contraceptive pill for men in a clinical trial. The progesterone stops sperm production in the testes, which lowers natural testosterone, so it’s added to the gel as well.

 The gel reduces sperm count when absorbed through the skin.
 Men rub it into their chest and shoulders as an easy alternative to a contraceptive pill. Men, right now have a very limited choice for contraception — using condoms or having a vasectomy. The latter one does not make for a good option if you want kids in the future. The clinical trial being conducted in Edinburgh and Manchester in the UK involves 450 couples who are required to use the gel as the main form of contraception for 12 months. Men participants apply a daily hormone-based gel to their chest, shoulders and upper arms as a prerequisite and condition of clinical trial. James Owers and Diana Bardsley, a couple in their 20s who are involved in the trial, spoke to the BBC about their experience so far.

 “I squeeze a 50p-piece-size out of the dispenser — the dispenser is a bit like one of those posh toothpaste tubes. It’s got the consistency of hand sanitizer,” said Owers.
 “I rub it into my shoulder and pectoral area and that dries in three to four seconds. I do that to the other shoulder and then I get dressed and go about my day as normal.” He added he’s been using it since February and has experienced very few side effects so far — a bit of acne on his back and about 1kg of weight gain.

 It takes 12 weeks of using the gel for a man’s sperm count to go all the way down, and another 12 weeks for it to go back up again. If effective, it could be significantly even more reliable than the female contraceptive pill, which can be ineffective if you miss just one day.
 “But if I was to miss taking this for an entire week, I would still be clinically infertile, so the risk here is quite different from the pill,” Owers said.

 As reported by INSIDER, the female contraceptive pill can have side effects like nausea, headaches, and breast tenderness, and inserting contraceptive implants can be painful. Also, some women cannot use hormonal birth control for health reasons.

 Similarly, clinical trials of male birth control pills have also had problems with side effects, including liver damage. Cheryl Fitzgerald, a consultant gynaecologist at Saint Mary’s Hospital, and leader of the study said she believed the contraceptive gel trial is an important step towards men controlling their fertility in a safe and simple way.

 Use of contraception is a common practice adopted by humans since decades to prevent pregnancy, beginning with the withdrawal method to a variety of techniques, medications, and devices. However technological advancement in contraception has conventionally focused on the woman as there are various alternatives available in the market such as many kinds of hormonal, barrier, intrauterine device and emergency contraceptive methods leaving men with only two main options: either using condoms or undergoing a vasectomy.

Tuesday, June 25, 2019

Comparing Intra-vaginal Culture of Embryos to In-vitro Culture of Embryos With Minimal Stimulation



Description

 SUMMARY

    The purpose of this study is to evaluate implantation rate with intra-vaginal culture with the INVOcell device versus traditional IVF while using minimal stimulation protocols

OFFICIAL TITLE
      Randomized Controlled Trial Comparing Intra-vaginal Culture of Embryos Using INVOcell Device to In-vitro Culture of Embryos Using Minimal Stimulation Protocols

 DETAILS

    This is a Phase IV, single center randomized controlled trial evaluating intra-vaginal culture using INVOcell versus traditional IVF using oral stimulation or minimal gonadotropin stimulation protocols. The pilot aims to includes 40 women who will be randomized to either the intra-vaginal culture group (N=20) using INVOcell or to the traditional IVF group (N=20). 

Primary aim is implantation rate, which is defined by number gestational sacs seen on early pregnancy ultrasound divided by number of embryos transferred.

Secondary aims are:

 Embryo quality, which is measured by the Gardner grading system.

 Fertilization rate, which is defined by the total number of fertilized oocytes divided by total number of mature oocytes retrieved. This comparison will take place on day-3, as that is when the IVC embryos will be assessed.

Clinical pregnancy rate, which is defined by the number of fetal poles with heartbeat seen on ultrasound divided by the number of embryos transferred.

 Live birth rate, which is defined by the number of living babies delivered divided by the number of transfers

Tuesday, June 11, 2019

Ovulation Induction


Ovulation Induction




Infertility is a painful journey to go through. But sometimes it can only be a temporary issue. One which can be resolved with proper treatment and support. Sometimes women’s bodies find it difficult to ovulate, or ovulate on an irregular basis. There are various reasons as to why this happens- stress, being over-weight, excessive exercise, hormonal imbalance, or problems with your reproductive system, to name a few. This is where Ovulation Induction comes in the picture.

 In this article, we will discussing about what Ovulation Induction is? How it works? And how do one cope with it?

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  What is Ovulation Induction?

Ovulation Induction is a medical treatment recommended for women who cannot ovulate by themselves. It basically stimulates the ovaries to produce an egg, which is later fertilized by a male’s sperm. Consult your physician and once you have ensured that you are having an ovulation problem, Ovulation Induction will help you restore your fertility- in other words, it will help you start ovulating again.


Multidisciplinary Treatment of Obesity Prior to in Vitro Fertilization: Impact on Global Reproductive Outcomes (PRO-FIV Study)

 How it works?

 Ovulation Induction involves taking fertility drugs in the form of tablets or injections. Only a small dosage may be needed to develop the Follicle Stimulating Hormone (FSH) which is will help the ovulation. The medications are to be taken at the beginning of your menstrual cycle and you will be monitored throughout with blood tests and ultrasounds. This will help determine when you are ovulating and provide you with the best time for conception. The doctor will ensure that your treatment is personalized according to your body’s needs.

Chronic Endometritis and IVF

 How do you cope with the process?

For your assurance, the success rate of modern fertility treatments is very high. But it takes patience and a calm mind to make sure you and your partner achieve your goal. If you are undergoing any stress then talk to your partner, know that they are with you. Distract yourself as much as you can. Plan a vacation and relax and let the good news come to you.

 Ovulation Induction has helped greatly in improving the chances of ovulation. However, there are various other treatments that you can opt for according to your needs. Talk to your physician and find the best solution for yourself. If you wish to know more about the process, you can read our eBooklet that gives you an in-depth account regarding Ovulation Induction








Thursday, May 9, 2019

Double Ovarian Stimulation as Accumulation Strategy for Older Infertile Patients With Suboptimal Ovarian Response



Brief description of study

Patients with infertility of the older age group of 37-42 years - a large cohort of patients of reproductive medicine. Two possible causes reduce their probability of pregnancy - an increasing age and a decrease of the ovarian reserve. In these conditions, the early receipt of embryos for future transfer can serve as a correct strategy for treating infertility in this category of patients. According to statistical data, patients of the 37-42-year-old age group need 3-5 blastocysts, out of them 1-2 euploid to achieve pregnancy.
The POSEIDON group of researchers identified a group of 2b patients with a suboptimal response to the induction of superovulation in IVF programs - patients older than 35 years with a normal ovarian reserve (the number of antral follicles greater than 5 and Anti-Mllerian hormone (AMH) greater than 1.2 ng / ml), resulting in 4-9 oocytes after a standard ovarian stimulation.
In this situation standard stimulation protocols can stretch the process of obtaining embryos indefinitely, during which the patient will move to another age category with a decrease in the likelihood of pregnancy.
Thus, these patients are shown the fastest reception of oocytes and the accumulation of embryos, which can be done using double ovarian stimulation in the same menstrual cycle.
The aim of the study is to compare the different schemes of double stimulation in patients with infertility of the older age group of 37-42 years with the preceding suboptimal response.
Group 1 - patients of the DUOSTIM group. Group 2 - Patients of the Shanghai Protocol.
The investigated parameters - primary outcome measures: total number of retrieved oocytes per cycle, secondary outcome measures: total number of blastocyst per cycle, number of cycles with double ovarian stimulation required to obtain 3-5 blastocyst, time until embryo transfer, pregnancy rate and birth rate This is a prospective randomized non-blinded clinical study.

Detailed Study Description

The aim of the study is to compare the different schemes of double stimulation in patients with infertility of the older age group of 37-42 years with the preceding suboptimal response.
Materials and methods. Patients with preserved ovarian reserve of 37-42 years old, who had the history of standard stimulation in IVF programs, which produce less 4-7 oocytes. Patients will be randomised in two groups. Group 1 - patients of the double ovarian stimulation in the same cycle with recombinant gonadotropin (DUOSTIM group). Group 2 - patients of the double ovarian stimulation in the same cycle with clomifen and recombinant gonadotropin (modified Shanghai Protocol).
The stimulation protocol in the Group 1 - Follitropin and Lutropin Alfa (Pergoveris) 150 -300 IU start from day 2 of the cycle up to the day of trigger, gonadotropin-releasing hormone (GnRH) antagonist 0,25 mg start from day 7-8 of the cycle up to the day of trigger, final trigger of ovarian stimulation - gonadotropin-releasing hormone agonist (GnRH-a) 0,2 mg, oocyte retrieval 35 hours after trigger, stop period for 5 days, after stop period start Pergoveris 150 - 300 IU start up to the day of trigger, GnRH antagonist 0,25 mg start from day 6 of ovarian stimulation up to the day of trigger, final trigger of ovarian stimulation - GnRH-a 0,2 mg, oocyte retrieval 35 hours after trigger.
After oocyte retrieval fertilization will be carried out by invitro insemination (IVI) or intracytoplasmic sperm injection (ICSI), the development of embryos will be carried out up to blastocyst stage, then blastocyst vitrification will be performed. The cycles of double ovarian stimulation will be performed until the patient will have not less than 3-5 blastocysts. Then the embryo accumulation process will be completed and the unfrozen embryos transferred in the hormonal replacement cycle or natural ovulatory cycle.
The stimulation protocol in the Group 2 - Clomiphene 50 mg start from day 2-3 of the cycle up to the day of trigger, Pergoveris 150 IU - 6,8, 10 days of the cycle, final trigger of ovarian stimulation - GnRH-a 0,2 mg, oocyte retrieval 35 hours after trigger, after stop period for 2-3 days start Pergoveris 150 - 300 IU up to the day of trigger, final trigger of ovarian stimulation - GnRH-a 0,2 mg, oocyte retrieval 35 hours after trigger. After oocyte retrieval fertilization will be carried out by IVI or ICSI, the development of embryos will be carried out up to blastocyst stage, then blastocyst vitrification will be performed. The cycles of double ovarian stimulation will be performed until the patient will have not less than 3-5 blastocysts. Then the embryo accumulation process will be completed and the unfrozen embryos transferred in the hormonal replacement cycle or natural ovulatory cycle.

Thursday, April 25, 2019

Time-restricted eating shows benefits for blood glucose




By restricting the time period during which they could eat, researchers have seen promising results for controlling blood glucose levels in men at risk of type 2 diabetes.

In a small study now published in the journal Obesity, researchers from the University of Adelaide and the South Australian Health and Medical Research Institute (SAHMRI) assessed the effects of time-restricted eating (TRE) in 15 men for one week.

"The men, who are at high risk of developing type 2 diabetes, limited their food intake to a nine-hour period per day," says Associate Professor Leonie Heilbronn from the University's Adelaide Medical School and SAHMRI.

"Participants undertook time-restricted eating either from 8.00am to 5.00pm or later in the day, from midday to 9.00pm. They ate their normal diet during this time," says Associate Professor Heilbronn. "In fact, we told them to keep eating all the foods they usually eat."

Blood glucose response to a standard meal was assessed each day of the study. The investigators found that TRE improved glucose control, regardless of when the men chose to stop eating.

"Our results suggest that modulating when, rather than what, we eat can improve glucose control.

"We did see a tiny amount of weight loss in this study, which may have contributed to the results," Associate Professor Heilbronn says.

Fred Rochler, who has been participating in a follow-up study, has undertaken a TRE regime in which he ate his normal diet only from 9.30am to 7.30pm over a similar eight-week trial.

"The restricted eating regime was initially challenging, but soon became more manageable," Mr Rochler says.

"I only ate up until 7.30pm as I found this worked well with my lifestyle.

"Over the trial, I found that my fasting blood glucose tolerance improved significantly. It changed from 'increased risk' level to 'normal'. This was without changing any of the foods that I like to eat," Mr Rochler says.

Associate Professor Heilbronn says: "Time-restricted eating regimes demonstrate that we can enjoy foods that are perceived to be 'bad' for us, if we eat them at the right time of day, when our bodies are more biologically able to deal with the nutrient load. And perhaps more importantly, if we allow our bodies to have more time fasting each night.

"While these early results show some promise for controlling blood glucose, a larger study over a longer duration is required to fully investigate the effectiveness of this pattern of time-restricted eating," she says.

Sunday, March 3, 2019

The Role of DNA Damage of Granulosa Cell on Oocyte Quality and in Vitro Fertilization Outcome


Brief description of study
Deoxyribonucleic acid (DNA) damage of granulosa cells obtained during oocyte retrieval will be evaluated by comet assay in unexplained infertile patients undergoing in vitro fertilization (IVF) treatment. The oocytes will be graded by particular criteria. Fertilization, embryo quality, transfer rate, implantation, clinical pregnancy, pregnancy outcomes (gestational age at delivery, route of delivery, and birthweight etc.) will be recorded as well as demographic data. DNA damage of granulosa cells will be compared between unexplained infertile and control groups. The effect of DNA damage of granulosa cells on fertilization, quality of oocyte and embryo, implantation, and clinical pregnancy will be also evaluated.

Detailed Study Description
Granulosa cells surrounding the oocytes will be mechanically obtained during the oocyte pick-up procedure in women undergoing in vitro fertilization (IVF) treatment due to unexplained infertility. Deoxyribonucleic acid (DNA) damage in these cells will be evaluated by comet assay. The quality of oocytes retrieved during the oocyte pick-up procedure will be graded by particular criteria (zona pellucida thickness, granulation, vacuolization, etc). Fertilization rates, embryo quality by grading, and transfer rates will also be assessed. Implantation and clinical pregnancy rates, and pregnancy outcomes including gestational age at delivery, route of delivery, and birthweight will be recorded as well as demographic data such as age, body-mass index, smoking, alcohol use, employment, coexisting chronic disease, infertility duration, etiology of infertility, treatment protocol, and hormone levels on day 3. Implantation will be evaluated by determination of serum human chorionic gonadotropin (hCG) at day 12 following an embryo transfer. Clinical pregnancy will be diagnosed upon presence of gestational sac on ultrasound examination. DNA damage of granulosa cells will be compared between unexplained infertile group and control group. The effect of DNA damage of granulosa cells on fertilization, quality of oocyte and embryo, implantation, and clinical pregnancy will be also evaluated.

Tuesday, February 19, 2019

Can Ibuprofen Delay Ovulation in Natural Cycle-IVF

Brief description of study

During natural cycle in vitro fertilisation, no gonadotropin stimulation is used to stimulate oocyte production. Ovulation is induced with HCG (human chorionic gonadotropin) and the follicle is retrieved 36 hours later.
In this study the patient in the intervention group will receive Ibuprofen as a study intervention beginning at the same time as the HCG injection. The treatment dose will either be 400mg every 8 to 12 hours or 800mg every 8 to 12 hours until the follicle retrieval, totalling 5 tablets. Instead of the usual time period of 36 hours, the follicular punction will occur after 42 hours. Should the oocyte still be accessible after this time period, then it is proven that Ibuprofen delays ovulation. In this case the patient will continue the regular NC-IVF treatment cycle.
The study design is a admissible two-stage design. During stage 1, 8 cycles in 8 patients will be examined. Should it be the case that after these 8 patients have completed a cycle, 4 or more show a positive treatment effect from the Ibuprofen intake, then the study will continue to stage 2 with 17 more more patients, totalling 25.
Should it be the case however, that after 8 patients, 3 or less show an effect of the Ibuprofen intake, then the study will be stopped prematurely for futility. The study intervention will be increased to 800mg of Ibuprofen and the study will recommence with 8 more patients.
A control group will consist of women undergoing intrauterine insemination (IUI) or timed sexual intercourse (TSI). 42 hours after Beta-HCG injection, an ultrasound examination will be performed in order to determine the number of remaining follicles in the ovary. This examination is to verify and control the proposed time limit of 42 hours.

Detailed Study Description

Background
In vitro fertilisation can be performed without the use of gonadotropin-stimulating medication, = Natural Cycle-IVF or NC-IVF for short. The effectivity of NC-IVF is limited as pro treatment cycle only one follicle develops, which can ovulate prematurely. If this is the case, a follicle aspiration is no longer possible and the next cycle must be awaited. One possibility of preventing premature ovulation is the prescription of NSAID, which is common practice in many centres, even though up until now, the effectivity has not been proven.
To test the meaningfulness of the worldwide implementation of NSAIDs in NC-IVF, a proof of concept is needed. An exactly defined study outline will explore the use Ibuprofen in a dosage of 3x400mg/24h or 3x800mg/24h. At the lower dose, Ibuprofen did not show increased side effects in randomised placebo-controlled studies.
The primary purpose of the study is therefore to determine whether or not NSAIDs in the form of Ibuprofen can successfully delay ovulation in such a way that it would be useful for everyday application in NC-IVF. Secondary purposes are to measure the effect of Ibuprofen on the Prostaglandin-E2 levels in the fluid of the extracted follicles and also whether the number of oocytes obtained in the extracted follicles differs from regular IVF-treatment.
The study design is a prospective, non-randomised, single-arm, no-treatment controlled, proof-of-concept trial. The intervention to be studied is a dose of either 400mg Brufen or a dose of 800mg Brufen (Drug class: Ibuprofen), taken every 8h (at night up to 12 hours) equalling a daily dose of 1200mg/24h or 2400mg/24h. The intervention will continue for 42h, totalling 5 tablets. Patients recruited will enter the study and take part for the duration of one NC-IVF treatment cycle, roughly for 2 months. Each patient can take part once, for one treatment cycle. The control group will consist of females undergoing either IUI or TSI treatment. One ultrasound examination will be performed, to measure the number of naturally occuring delayed ovulation, 42h after HCG injection. Patients recruited can take part once, for one treatment cycle.
The study population will include females between the ages of 18-42, with an indication for NC-IVF, IUI or TSI. They must wish for this treatment and fulfil all the necessary requirements, such as a regular menstruation every 26-32 days and the accessibility of both ovaries for the transvaginal follicular puncture.
The study intervention is planned with 25 completed cycles in 25 individual patients and two interim analyses which allows stopping of the trial for futility potentially after the first 8 completed cycles (two-stage design). The study control is planned with 25 treatment cycles in 25 individual patients. Blinding will not occur, as no placebo or non-historical test group will be used, thus it is an open trial.
No randomisation or stratified sampling will occur. Patients who qualify will be recruited in the NC-IVF, IUI or TSI consultations in our own Clinic.
The total study for the intervention group will span 5 consultations:
  • Consult 1: Recruitment of patients, description of study and hand out of patient information informed consent documentation.
  • Consult 2: Day 8-14 of the Patients' menstrual cycle. Collection of informed consent documentation and definitive enrollment in study. The patients undergo a sonographic examination of the follicle size as well as determination of E2 and LH serum levels. Following the consultation, the patients will self-inject the HCG and at the same time commence the study intervention of 400mg Brufen every 8 hours until Consult 3.
  • Consult 3: Exactly 42h after the HCG injection, the patients undergo a sonographic check of the follicle and if it remains unovulated, then it will be retrieved via vaginal access. Along with the OPU, the second study intervention in form of a 5ml venous blood sample will take place, in order to determine the serum levels of Ibuprofen.
  • Consult 4: If a follicle was retrieved and successfully fertilised, 2-3 days later it will be transferred in the patients' uterus-
  • Consult 5: 14-18 days after the embryo transfer, the patients will perform a pregnancy test.
Should after 8 completed cycles the dose of 400mg Brufen not be able to show the effect of delaying ovulation in >3 of the 8 study participants, then the treatment dose will be raised to 800mg Brufen and the study recommences.
The total study for the control group IUI will span 5 consultations:
  • Consult 1: Recruitment of patients, description of study and hand out of patient information informed consent documentation.
  • Consult 2: Day 8-14 of the Patients' menstrual cycle. Collection of informed consent documentation and definitive enrollment in study. The patients undergo a sonographic examination of the follicle size as well as determination of E2 and LH serum levels. Following the consultation, the patients will self-inject the HCG.
  • Consult 3: Exactly 36h after the HCG injection, the patients undergo intrauterine insemination.
  • Consult 4: Exactly 42h after the HCG injection, the patients undergo a sonographic check of the follicle, to see if it remains unovulated.
  • Consult 5: 14-18 days after the embryo transfer, the patients will perform a pregnancy test.
The total study for the control group TSI will span 4 consultations:
  • Consult 1: Recruitment of patients, description of study and hand out of patient information informed consent documentation.
  • Consult 2: Day 8-14 of the Patients' menstrual cycle. Collection of informed consent documentation and definitive enrollment in study. The patients undergo a sonographic examination of the follicle size as well as determination of E2 and LH serum levels. Following the consultation, the patients will self-inject the HCG. 24-48h after HCG injection, the patients have sexual intercourse.
  • Consult 3: Exactly 42h after the HCG injection, the patients undergo a sonographic check of the follicle, to see if it remains unovulated.
  • Consult 4: 14-18 days after the embryo transfer, the patients will perform a pregnancy test.
Justification of the study design:
Large studies including one prospective randomised study using NSAIDs versus no medication have been performed to test the efficacy of NSAIDs. However, the study designs have been proven not to be useful to test the hypothesis that NSAIDs delay the ovulation.
Therefore the only design which will prove this hypothesis is the ovulation induction followed by a follicle aspiration so late that the follicle will definitely have been ovulated. If patients take Ibuprofen and the follicle has still not ovulated 42 hours after ovulation induction, the hypothesis will be confirmed. The time limit of 42h shall be verified by a control group, consisting of a similar patient collective as the intervention group.
Objective
  • Overall Objective The purpose of this study is to evaluate whether Ibuprofen delays ovulation in such a manner that it can be used effectively in patients undergoing NC-IVF treatment and aims to describe an efficacy and safety profile for Ibuprofen in this context.
  • Primary Objective The study seeks primarily to determine whether Ibuprofen can delay ovulation, in order to reduce the rate of premature ovulations in NC-IVF.
  • Secondary Objectives A secondary objective is to analyse if Ibuprofen inhibits the detachment of the oocyte from the follicular wall leading to a reduced oocyte yield.
A secondary objective is to analyse the rate of delayed ovulation in the control group, after induced ovulation by HCG injection.
Methods
As a first study intervention the patient will receive 400mg of Ibuprofen every 8-12 hours until the morning of the day of the planned follicular extraction. This is the equivalent of 5 tablets beginning at the time of the HCG injection, which induces ovulation. The follicular extraction will not take place after 36 hours which is usually the case, but after 42 hours after HCG injection.
In the case of the trial being stopped for futility after the first 8 completed cycles, the treatment dose of Ibuprofen will be increased to 800mg and the study will recommence.
Should the follicle not already have ovulated then the treatment will continue as a regular IVF therapy (with the fertilisation of the oocyte and the following embryo transfer).
As a second study intervention, all patients will give a blood sample (5ml) at the time of follicle extraction in order to determine the serum concentration of Ibuprofen, thus proving that it was taken.
The control group will undergo an ultrasound examination to determine whether or not an unruptured follicle is still present in the ovary, 42h post HCG-injection.

Monday, February 4, 2019

Can Calcium Ionophore Application Enhance the ICSI Outcomes in Severe Male Factor Infertility?




Brief description of study

The purpose of this study is to determine the impact of the use of calcium ionophore on the ICSI outcomes in couples with severe male factor infertility. Investigators conduct a randomized controlled trial on the sibling oocyte to justify the use of calcium ionophore in these cases.

 Detailed Study Description

Elevation of calcium levels inside the oocyte is one of the most initial steps which takes place during normal fertilization . The interaction between the sperm and oocytes surface protein receptors may be the triggering event for oocyte activation during the process of fertilization . It is suggested that the process of intracellular Calcium elevation is triggered by binding of the sperm to the oocyte oolemma and hence the fertilization starts . Severe male factor couples might have compromised fertilization and pregnancy outcomes.

A prospective multicenter non-randomized study indicated that calcium ionophore could improve the fertilization as well as the clinical pregnancy rates in these patients . On the other hand, a randomized controlled trial did not find any significance for the use of calcium ionophore in the couples with poor ovarian reserve with regards the fertilization and clinical pregnancy rates . The purpose of this study is to determine the impact of the use of calcium ionophore on the ICSI outcomes in couples with severe male factor infertility. Investigators conduct a randomized controlled trial on the sibling oocyte to justify the use of calcium ionophore in these cases.

Saturday, February 2, 2019

Impact of Virtual Reality Before Oocytes Retrieval on Anxiety and Pregnancy Rate


Brief description of study


 The primary objective of this study is to evaluate the impact of a session of virtual reality (VR) with the objective of lowering the anxiety level on the clinical pregnancy rate following an In-vitro fertilisation (IVF) procedure. Indeed, anxiety in relation to infertility happens frequently and over time, can become stressful for our patients. This level of stress influences the effect of the infertility treatment. Reducing anxiety levels could promote the ability of the patients to face this stress and promote a greater chance of pregnancy in that context.

Sunday, January 27, 2019

Multidisciplinary Treatment of Obesity Prior to in Vitro Fertilization: Impact on Global Reproductive Outcomes (PRO-FIV Study)



Brief description of study

   The aim of the present study is to evaluate the impact of a multidisciplinary treatment of obesity prior to IVF on global reproductive outcomes and maternofetal metabolic and cardiovascular risk factors.
     This is a randomized controlled trial in obese infertile women before starting an IVF cycle. The intervention is based on a structured multidisciplinary program in support groups, which includes diet, physical activity and psychological therapy. IVF will be started immediately after this therapy. Patients included in the control group will start an IVF cycle immediately after the randomization. The results of this study may allow the identification of patients who would benefit from obesity treatment, so as to establish appropriate preventive and therapeutic strategies and to reduce the maternal obesity impact in future generations.

 Detailed Study Description

 The aim of the present study is to evaluate the impact of a multidisciplinary treatment of obesity prior to IVF on global reproductive outcomes and maternofetal metabolic and cardiovascular risk factors.
      This is a randomized controlled trial in obese infertile women (body mass index 30 kg/m2) before starting an IVF cycle. In the intervention group, the aim is a weight loss of at least 10% in a 16-week period of treatment based on a multidisciplinary approach and support groups, which includes diet, physical activity and psychological therapy. IVF will be started immediately after this period. Patients included in the control group will start an IVF cycle immediately after the randomization. The results of this study may allow the identification of patients who would benefit from obesity treatment, so as to establish appropriate preventive and therapeutic strategies and to reduce the maternal obesity impact in future generations.

Friday, January 18, 2019

Chronic Endometritis and IVF



Brief description of study
 Background:
Embryo quality is known to be a very important determinant to predict the implantation and pregnancy rate in IVF patients, however, the role of uterine integrity or endometrial receptivity cannot be overlooked. Chronic endometritis (CE) is an inflammation of the endometrium diagnosed by the presence of plasma cells in the endometrial stroma. There is not only no census on the definition of CE, the current literature on the impact of CE on reproductive outcome is controversial and consists only of retrospective studies with small sample sizes. Although there is a presumption that CE is related to poor IVF outcome, this belief has not been proven.

 Design:
 Prospective cohort study

 Setting:
 Infertility clinics of 2 academic medical centers

 Patients:
 Patients between the ages of 21 and 35 years old undergoing their first IVF cycle will be invited to participate.

 Main Outcome Measures:
The primary outcome will be ongoing pregnancy after 12 weeks estimated gestational age (EGA) with previously documented fetal cardiac motion. Secondary outcomes will include pregnancy loss rate as defined by chemical pregnancy, blighted ovum or loss of fetal cardiac motion before 12 weeks EGA.

 Materials and Methods:
The cycle prior to IVF, patients will undergo an in-office endometrial biopsy on cycle days 19-24. Samples will be stained for CD138 and the number of plasma cells will be quantified. The number of plasma cells in a sample that yields the best sensitivity and specificity for pregnancy will be determined by a Receiver-Operator-Curve. This number will then be used as a dichotomous variable to assign categories of "positive for CE" and "negative for CE." Pregnancy and miscarriage rates will then be determined in the positive and negative CE sample with Chi Square Analysis. A secondary sub analysis will be performed to determine pregnancy and miscarriage rates in patients who declined to participate in the study.

 Expected Results:
 The investigators hypothesize that higher rates of CE will be found in women failing to conceive with IVF and with subsequent first-trimester miscarriage.

Thursday, January 17, 2019

Conversion of in Vitro Fertilization Cycles to Intrauterine Inseminations in Patients With a Poor Ovarian Response to Stimulation


Brief description of study
The purpose of this study is to compare the efficiency of conversion to IUI and IVF in patients with a poor ovarian response to stimulation

Detailed Study Description
In 5 to 10% of in vitro fertilization (IVF) cycles, a poor response to ovarian stimulation (defined as less than 4 mature follicles) is noted, even though high doses of exogenous gonadotropins are used. To date, there is no consensus on the ideal management strategy in poor responders. There are three therapeutic options available nowadays:

Oocyte retrieval is performed and the IVF cycle continued, despite the low number of mature follicles.
Conversion of the IVF cycle to an intrauterine insemination (IUI), on the condition of having at least one patent fallopian tube and good semen parameters.
Cancelation of the IVF cycle. In everyday practice, it is difficult for the physician to cancel the IVF cycle in the presence of 2, 3 or 4 mature follicles, especially following a lengthy stimulation.
If live birth rates were comparable between IUI and IVF, conversion to IUI would be the better option for poor responders, since it would avoid an invasive procedure (oocyte retrieval) and the associated risk of complications, and is associated with at a lower cost.

To our knowledge, no prospective randomized controlled trial comparing IVF to conversion to IUI in poor responders has been published to date. The studies published so far have been retrospective and observational, and had several methodological flaws.

Therefore, we aimed to analyze whether conversion of IVF cycles to IUI in poor responders would result in the same live birth rates as oocyte retrievals followed by embryo transfers.

Tuesday, January 15, 2019

In Vitro Fertilization Impact on Metabolic Parameters


Brief description of study

A quantitative prospective cohort study will be conducted, where blood samples will be collected at different timings during the IVF protocol, to assess the impact of fertility medications on metabolic parameters of patients undergoing IVF treatment.

Detailed Study Description

Numerous factors predispose women to develop pregnancy-related complications, these include gestational diabetes (GDM), pre-pregnancy obesity, advanced maternal age (> 35 years) and gestational age, abnormal weight gain during pregnancy, family history of diabetes, PCOS and low parity. Evidenced-based studies reported that women with PCOS have a significantly higher risk of developing GDM compared with women without PCOS, independently of the obesity factor; this risk is higher when both factors coexist.
Given the known effect of reproductive hormones on weight-gain, controversies still exist on whether ART predispose women to more adverse obstetric outcomes compared to normal pregnancy. ART describes different procedures to help women become pregnant, with In Vitro Fertilization (IVF) being the most commonly performed. It has been demonstrated that IVF is associated with glucose intolerance in mice and it will be interesting to determine whether this physiologic phenomenon is also altered by IVF medication (such as estrogen and progesterone) in humans. While some studies reported that singleton pregnancies conceived by ART (IVF or ovulation induction) were strongly associated with GDM compared to spontaneous conceptions, other studies did not find significant differences in the risk of GDM. Increased GDM risk presented with IVF can be associated with prenatal obesity or secondary to maternal PCOS condition. The former studies did not specify the body mass index (BMI) and the medical history of participants undergoing IVF, such as the presence of PCOS. Due to limited available data, we still cannot distinguish whether these adverse pregnancy outcomes are due to the pre-existing conditions such as PCOS, or are secondary to the IVF therapy itself.

Saturday, January 5, 2019

USFDA approved Annovera (segesterone acetate andethinylestradiolvaginal system)



General Information

 Annovera contains two active components, a progestin - segesterone acetate, and an estrogen - ethinyl estradiol. Both components work together to suppress ovulation. Annovera is specifically indicated for use by females of reproductive potential to prevent pregnancy. Annovera is supplied as a vaginal ring for intravaginal administration. One Annovera is inserted in the vagina. The vaginal system must remain in place continuously for 3 weeks (21 days) followed by a 1-week (7-day) vaginal system-free interval. One vaginal system provides contraception for thirteen 28-day cycles (1year). Please see drug label for specific insertion directions.

 Clinical Results
 FDA Approval
 The FDA approval of Annovera was based on two 1-year multicenter trials enrolling 2,265 females, age 18–40 years, who were healthy and sexually active with regular menstrual cycles. Based on pooled data from the two trials, 2,111 females ≤35 years of age completed 17,427 evaluable 28-day cycles (cycles in which no back-up contraception was used).The pooled pregnancy rate, evaluated by the Pearl Index (PI),was 2.98 per 100 woman-years of Annovera use. Return to fertility was assessed in 290 of the subjects in the two trials who either desired pregnancy or switched to a non-hormonal method after the trials, and all 290 subjects reported a return to fertility during the 6-month follow-up period (defined as a return of menses or pregnancy).

 Side Effects
Adverse effects associated with the use of Annovera may include, but are not limited to, the following:
 headache/migraine
 nausea/vomiting
 vulvovaginal mycotic infection/candidiasis 
abdominal pain lower/upper dysmenorrhea vaginal discharge
 urinary tract infection
 breast tenderness/pain/discomfort
 bleeding irregularities including metrorrhagia diarrhea
 genital pruritus
 The Annovera label comes with the following Black Box

Warning:
Females over 35 years old who smoke should not use Annovera. Cigarette smoking increases the risk of serious cardiovascular events from combination hormonal contraceptive use. Mechanism of Action Annovera (segesterone acetateand ethinyl estradiolvaginal system) is a ring-shaped, nonbiodegradable, flexible, opaque white vaginal system containing two active components: a progestin - segesterone acetate, and an estrogen - ethinyl estradiol. When placed in the vagina, each Annovera releases an approximate average 0.15mg/day of segesterone acetate and 0.013mg/day of ethinyl estradiol over the21 days in-use period of each cycle for up to 13 cycles (total of 273 days). Each cycle is 28 days, with 21 days in and 7 days out. The two components work together to suppress ovulation.

Transvaginal vs Transabdominal Ultrasound Guided Embryo Transfer

Brief description of study

Embryo transfer is the last step in the IVF process. it is now recognized that this step should be done carefully and that it affects success rates. in recent years, sonographic guidance appears to increase success rates.

Detailed Study Description

Embryo transfer is the last step in the IVF process. it involves the insertion of a soft catheter through the uterine cervix. It is now recognized that this step should be done carefully and that it affects success rates. The embyos should be carefully deposited in the cavity. special care should be given to avoid touching the uterine fundus during the procedure. In recent years, sonographic guidance appears to increase success rates.

Thursday, January 3, 2019

Comparison of Two Embryo Transfer Catheters in Patients Undergoing in Vitro Fertilization and Embryo Transfer



Brief description of study
In-vitro fertilization (IVF) treatment involves development of multiple follicles following ovarian stimulation, oocyte retrieval and embryo transfer (ET). ET is the final and most crucial step of IVF treatment.

The ET catheter has to pass through the endocervical canal to go into the uterine cavity through the internal os. The endocervical canal may be filled up with mucus or blood. Embryos trapped in the mucus or blood after the passage of the endocervical canal may not be able to implant into the endometrium. Guardia Pro Protective ET catheter is designed to allow the safe passage of embryos through cervical mucus and blood as its outer sheath protects the embryo through entry and then opens in petals to further advance the inner catheter and gently place the embryo.

The hypothesis of this study is that the pregnancy rate is significantly higher after ET using protective ET catheters.

Detailed Study Description
In-vitro fertilization (IVF) treatment involves development of multiple follicles following ovarian stimulation, oocyte retrieval and embryo transfer (ET). Despite recent advances in ovarian stimulation, the method of assisted fertilization and improved culture conditions, the implantation potential of embryos remains around 20-25% for a long time.

ET is the final and most crucial step of IVF treatment and pregnancy rates after ET may be affected by various factors. In a Cochrane meta-analysis (Derks et al., 2009), no evidence of a benefit was found for performing ET with a full bladder, the removal of cervical mucus, and flushing the endocervical canal or the endometrial cavity. No data were found on changing the woman's position, the use of a tenaculum, the performance of a dummy transfer, and embryo afterloading. Other meta-analyses demonstrate that the use of soft ET catheters (Buckett, 2008) and transabdominal ultrasound guidance (Brown et al., 2010) lead to a higher chance of clinical pregnancy when compared with the use of stiff catheters and clinical touch respectively.

The ET catheter has to pass through the endocervical canal to go into the uterine cavity through the internal os. The endocervical canal may be filled up with mucus or blood. Embryos trapped in the mucus or blood after the passage of the endocervical canal may not be able to implant into the endometrium. Guardia Pro Protective ET catheter is designed to allow the safe passage of embryos through cervical mucus and blood as its outer sheath protects the embryo through entry and then opens in petals to further advance the inner catheter and gently place the embryo.

There is still no study comparing conventional and protective ET catheters in terms of the pregnancy rate of IVF treatment. The hypothesis of this study is that the pregnancy rate is significantly higher after ET using protective ET catheters.

Research plan Patients attending the Department for IVF-ET will be recruited if they fulfill the inclusion criteria and do not have the exclusion criteria. The FET treatment will be arranged as indicated.

On the day of ET, patients will be randomized according to a computer-generated randomization list in sealed envelopes into two groups: conventional and protective ET catheter groups. Conventional ET catheters will be used in the conventional ET catheter group while protective ET catheters will be used in the protective ET catheter group. Patients would be blinded to the group assigned although the clinical, nursing and laboratory staff will be aware of the type of catheters used.

A maximum of two good quality embryos are to be replaced. Patients are asked to keep a mildly full bladder so that the uterus can be visualized by abdominal sonogram during the procedure. A bivalve speculum is inserted into the vagina and the cervix is cleaned with warm saline and culture medium. The axis, degree of flexion and the configuration of the uterine cavity are determined by transabdominal ultrasound examination before the transfer. Under transabdominal ultrasound guidance, the outer catheter is inserted into the cervical canal 4 cm from the external os, with the tip just beyond the internal os. A malleable obturator is used if difficulty is encountered. The inner transfer catheter with the loaded embryo(s) is then inserted into the uterine cavity via the outer cannula. The aim is to put the tip of the inner catheter inside the uterine cavity 6 cm from the external os and care was taken not to advance the tip beyond 1 cm from the uterine fundus. The transfer volume is gently expelled by the technician. The catheters will be held in place for 30 seconds. Both the inner and outer catheters will be checked by the technician under the microscope to make sure that the embryos have been replaced.

The luteal phase support will be used if needed and antenatal management is as usual, if pregnant.

Sample size estimation The ongoing pregnancy rate of IVF-ET in 2010 was about 30.0%. Assuming a 10% increase following use of protective ET catheters as significant, 356 patients in each arm was required at a power of 80% and a significance level of 5% (Sigmastat, Jandel Scientific, San Rafael, CA, USA). A total of 720 patients will be recruited into the study.

Interim analysis will be performed after recruitment of every 100 subjects

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