Caesarean section defect : what happens - review of a paper
Reproductive Implications of Uterine Niches Following Cesarean Section
Abstract:
Uterine niches, representing the myometrial discontinuity or defect at the site of a prior Cesarean section scar, have been posited to have deleterious implications on subsequent fertility and pregnancy outcomes. This narrative review synthesizes the existing literature delineating the multifaceted manner in which uterine niches may impede sperm penetration, embryo implantation, and embryo transfer, alongside the psychogenic factors potentially diminishing the likelihood of conception. The elucidated mechanisms encompass alterations in the intrauterine environment, modified immunobiological responses, uterine contractility disturbances, and physical barriers stemming from niche-associated anatomical deviations. Additionally, the psychosocial impact of niche-related gynaecological symptoms and their respective therapies are discussed in the context of fertility implications.
Introduction:
The presence of a uterine niche following Cesarean section has garnered attention due to its potential adverse effects on subsequent reproductive outcomes. The mechanisms underlying these reproductive hurdles are diverse, ranging from altered uterine anatomy to psychogenic factors. This review delineates the existing hypotheses underpinning the detrimental reproductive consequences associated with uterine niches.
Intrauterine Fluid Accumulation:
The accumulation of intrauterine fluid within the niche may foster an inhospitable environment for embryo implantation. This milieu may hinder the requisite apposition and adherence of the embryo to the endometrial lining, thereby thwarting successful implantation.
Immunobiological Alterations and Inflammatory Responses:
The presence of a niche may trigger altered immunobiological responses or exacerbate intrauterine inflammation. Such alterations may impair the fine-tuned immune tolerance necessary for successful embryo implantation and early pregnancy sustenance.
Uterine Contractility Disturbances:
Niches may induce fibrosis or disrupt the myometrial layer, leading to distorted uterine contractility. This aberration may impair sperm transit through the uterine cavity and fallopian tubes, potentially impeding fertilization.
Mucus and Hematological Debris Accumulation:
The accumulation of mucus and old blood within the niche may pose a barrier to sperm penetration, further diminishing the likelihood of successful fertilization.
Anatomical Barriers to Embryo Transfer:
A pronounced niche, especially in conjunction with a severely retroflexed uterus, may distort uterine anatomy significantly, thereby impeding the accessibility for embryo transfer during assisted reproductive techniques.
Psychogenic Impediments to Conception:
Niche-associated gynaecological symptoms may deter sexual activity, and the ensuing medical interventions aimed at alleviating niche complaints may, in turn, restrict the opportunities for conception during the convalescence period.
Conclusion:
The multifaceted reproductive ramifications of uterine niches underscore the necessity for comprehensive evaluation and management of women with prior Cesarean sections, especially those manifesting niche-related symptoms or encountering fertility hurdles. The confluence of physical and psychogenic factors elucidated herein necessitates a multidisciplinary approach to optimize reproductive outcomes in this cohort.
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Calcium Activation in IVF a simple explanation for clinicians
The challenges faced in ART (Assisted Reproductive Technology) include the failure of embryos to thrive or establish full-term pregnancies, deficiencies in technology for a subset of patients seeking assistance, complexities of oocyte activation, limitations in the understanding of fundamental principles of human reproductive biology, and the need for more discriminating and rigorously designed studies tracking live birth rates and long-term health outcomes.
Additionally, there is a need for distinguishing between the available and "ready to use" evidence and the era of misinformation or disinformation prevalent today.
What is oocyte activation ?
Oocyte activation is the process by which an egg is triggered to begin dividing and developing into an embryo. It is triggered by the sperm entering the egg and releasing a number of proteins. These proteins cause a cascade of events that lead to the egg dividing.
The first step in oocyte activation is the release of calcium ions from the egg's cytoplasm. This is caused by the sperm's proteins binding to receptors on the egg's surface. The calcium ions then trigger a number of other events, including the breakdown of the egg's zona pellucida, the release of the second polar body, and the activation of the egg's genome.
Once the egg is activated, it begins to divide. The first division takes about 30 minutes, and the second division takes about 2 hours. After the second division, the embryo is called a zygote. The zygote then continues to divide and develop into a blastocyst, which is a ball of cells that implants in the uterus.
Oocyte activation is a critical step in the process of reproduction. Without oocyte activation, the egg would not be able to divide and develop into an embryo.
Understanding oocyte activation
Calcium oscillations play a crucial role in oocyte activation. During fertilization, the sperm triggers a series of calcium oscillations in the oocyte, which are essential for the completion of meiosis and the initiation of embryonic development. These calcium oscillations are necessary for the release of cortical granules, which prevent polyspermy and modify the zona pellucida to prevent further sperm from binding. In the absence of fertilization, artificial activation of the oocyte can be achieved by inducing calcium oscillations using ionophores or other methods. The frequency and amplitude of calcium oscillations are critical for successful oocyte activation and subsequent embryonic development.
What are the limitations and the risk of Calcium activation ?
Current oocyte activation treatments, such as the use of ionophores, have limitations. The effectiveness of these treatments can vary widely between patients, and even within a single patient cohort, which is a limitation.
In addition, the use of ionophores is associated with potential risks and side effects, such as oocyte or embryo damage and the induction of abnormal calcium oscillations, which can result in developmental abnormalities. In addition, the mechanisms underlying oocyte activation are not fully understood, and more research is required to identify new intervention targets.
Lastly, there are no standard protocols for oocyte activation, and additional research is required to optimise treatment strategies and improve outcomes for patients undergoing assisted reproductive technology (ART).
From Constraints imposed by the complexities of oocyte activation
David F. Albertini
ournal of Assisted Reproduction an ournal of Assisted Reproduction and Genetics (2022) 39:1217–1218d Genetics (2022) 39:1217–1218
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WHO advises not to use non-sugar sweeteners for weight control in newly released guideline
The World Health Organization (WHO) has published a fresh set of guidelines concerning non-sugar sweeteners (NSS), strongly advising against their usage as a means to manage weight or decrease noncommunicable diseases (NCDs) risk.
These guidelines draw on a comprehensive analysis of existing research, which indicates that NSS do not deliver long-term advantages in curbing body fat in either adults or children. The review's findings also hint at possible adverse outcomes from chronic NSS usage, including a heightened probability of type 2 diabetes, cardiovascular ailments, and mortality among adults.
Francesco Branca, the WHO Director for Nutrition and Food Safety, stated, "Substituting free sugars with NSS isn't a long-term weight control solution. People should explore alternate methods to lower free sugar consumption, like incorporating naturally sweet foods such as fruits, or opting for unsweetened food and beverages." He added, "NSS do not play an essential role in our diet and offer no nutritional value. We should aim to decrease the overall sweetness in our diets from an early age to promote better health."
The guidelines are applicable to everyone except those with pre-existing diabetes and involve all synthetic, naturally occurring, or modified non-nutritive sweeteners not classified as sugars in processed food and drinks, or those sold separately for consumer usage. NSS typically includes substances like acesulfame K, aspartame, advantame, cyclamates, neotame, saccharin, sucralose, stevia, and its derivatives.
The guidelines do not extend to personal hygiene and care products containing NSS, such as toothpaste, skin creams, and medications, or low-calorie sugars and sugar alcohols (polyols). The latter are sugar or sugar derivatives with caloric content, hence not regarded as NSS.
Given the potential confounding variables in the correlation observed between NSS use and disease outcomes in the research, the guidelines are rated as conditional per WHO's guideline development process. This signifies that policy decisions inspired by these guidelines may necessitate thorough discussions within individual country contexts, possibly connected to consumption rates across different age groups.
These new WHO guidelines on NSS are part of an array of existing and upcoming healthy diet guidelines aiming to foster lifetime healthy eating habits, boost dietary quality, and decrease NCDs risk globally.
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Luteal phase defect a short summary LPD
LPD stands for luteal phase deficiency, which is a condition where the progesterone produced by the corpus luteum is not sufficient to maintain the endometrium and support pregnancy.
Is luteal phase defect controversial ?
Its existence is controversial because there is a lack of uniform criteria for its diagnosis, and the data proving LPD as an independent entity causing infertility in spontaneous cycles is not enough.
Why is detecting LPD in nature difficult ?
Additionally, the timing of ovulation is difficult to measure accurately, endometrial histological readings are often subjective, and there are no common thresholds for optimal progesterone concentration.
Is it all about the corpus luteum ?
LPD can also reflect a defect of the embryo and low hCG secretion, not just the performance of the corpus luteum itself.
The challenges in diagnosing LPD include:
Lack of uniform criteria: There is no standard approach to diagnose LPD, and the criteria for LPD vary between different publications.
Difficulty in measuring ovulation: The actual timing of ovulation is difficult to measure accurately, even when measuring urinary LH peaks.
Subjectivity of endometrial histological readings: Endometrial histological readings are often subjective, time-consuming, and variable between readers, with poor correlation to fertility.
Lack of common thresholds for optimal progesterone concentration: There are no common thresholds for optimal progesterone concentration, mainly due to a lack of strong data showing a link between low progesterone levels and delayed time to pregnancy or infertility.
LPD can reflect a defect of the embryo: As corpus luteum function is maintained by hCG produced by the conceptus, LPD can also reflect a defect of the embryo and low hCG secretion, not just the performance of the corpus luteum itself.
Does Low egg reserve lead to LFD?
A study by Pfister et al. evaluated the association of ovarian reserve markers and the occurrence of LPD to determine if ovarian aging and diminished ovarian reserve produce a risk for the condition.
The study found that AMH did not predict luteal phase bleeding or short luteal phase. Low early follicular phase FSH levels and high early follicular phase estradiol increased modestly the risk for luteal phase bleeding.
Moreover, the risk for short luteal phase decreased with increasing levels of inhibin B. Given that AMH is a more sensitive marker for ovarian aging compared to FSH and inhibin B, this data provides the best evidence that there is no link between ovarian aging and LPD.
Summarized from luteal phase defect Fertil steril 2019
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Understanding sperm DNA fragmentation
DNA damage in sperm can come from many different outside sources, like
• UV and ionising radiation and genotoxic chemicals,
• as well as from inside the body, like reactive oxygen species (ROS) and DNA polymerase mistakes.
There are many different kinds of damage that can be caused by these insults, and different agents tend to cause different kinds of DNA damage.
. Most damage to spermatozoa is caused by three things:
• bad chromatin condensation during spermiogenesis,
• failed apoptosis, and
• oxidative stress.
Chromatin remodelling during spermiogenesis causes chromatin condensation defects. The goal of this process is to pack the DNA into the smallest possible shape, which changes the size of the sperm head into the best shape for movement.
Endonucleases (like caspases) are responsible for breaking down DNA, but they are unable to access the nucleus in sperm because the mitochondria and nucleus are located in different parts of the cell. Thus, mitochondrial ROS are the primary trigger of apoptosis in sperm.
What Happens with Apoptotic sperm?
Apoptotic spermatozoa are less mobile and have reduced fertility, but they can still fertilise an egg. This can cause problems during embryo development or even result in a miscarriage if sperm contains DNA damage..
What can change DNA FRAGMENTATION?
Diet, exercise, and smoking all affect reactive oxygen species (ROS) levels, which in turn affects male fertility. Sperm quality can decline with age. The DNA in sperm from older men is more fragmented, making them less mobile than sperm from younger men.
What is the impact of DNA fragmentation on embryo development ?
Sperm DNA damage can be detrimental to embryo development. The risk of infertility, spontaneous abortion, or a low-quality embryo is correlated with the severity of the damage.
Zygotes fertilised by damaged sperm still have a chance of blastulating and developing into a pregnancy, but the success rate is lower.
This is probably due to the low level of transcriptional activity in spermatozoa.
Extremely high levels of genotoxic insults, however, render sperm cells incapable of fertilising oocytes. The plasma membrane of the sperm is being harmed by peroxides, which is why this is happening. Human oocytes' resistance to damage is less well understood than that of spermatozoa.
DNA ASSESMENT TESTS : how many tests are there ?
In the comet assay, DNA damage is detected by running single cells through an electrophoresis machine. Sperm and embryos can be tested for DNA damage with this method.
The terminal deoxynucleotidyl transferase (TUNEL) assay is a test for detecting DNA damage in cells by using an enzyme that has been fluorescently labelled.
The sperm chromatin structure assay (SCSA) detects DNA damage by measuring the sensitivity of sperm chromatin to acid.
The DNA fragmentation index (DFI) measures the percentage of fragmented sperm DNA through the use of flow cytometry.
DNA damage in embryos can be detected by a test that counts the number of copies of mitochondrial DNA.
The development of an embryo can be tracked over time with the help of time-lapse photography. Issues with cell division and other aspects of development may be indicated.
When deciding which embryos to transfer in assisted reproductive technologies, we can learn a lot about their DNA using these non-invasive methods.
Views from
DNA damage in preimplantation embryos and gametes: specification, clinical relevance and repair strategies".
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Lets summarise the general evidence and key findings regarding myoinositol and metformin for you.
1. Myoinositol: Myoinositol, a substance that occurs naturally, has been investigated for the possible positive effects it may have on PCOS patients.
• A meta-analysis by Unfer et al. (2012) concluded that myoinositol supplementation improved ovulation and metabolic parameters in women with PCOS.
• Other studies have shown that myoinositol supplementation may improve insulin sensitivity and reduce insulin resistance. For instance, Costantino et al. (2009) discovered that adding myoinositol to a woman's diet improved her insulin sensitivity. This was observed in PCOS patients.
• Nordio and Proietti (2012) conducted a randomised controlled trial comparing myoinositol to metformin in women with PCOS and found that both treatments improved hormonal and metabolic parameters, but myoinositol was better tolerated with fewer side effects.
• On the other hand, it is important to point out that additional research is required if we are going to have a complete understanding of the effects myoinositol has over the long term as well as the appropriate dosages.
2. Metformin: - Metformin is an oral medication commonly used to treat type 2 diabetes and has been investigated for its effects on PCOS and metabolic disorders.
• In women who have polycystic ovary syndrome (PCOS), taking metformin has been shown to improve menstrual irregularities and ovulation, according to a review that was conducted by Tang et al. (2012). Several studies have demonstrated that metformin can reduce insulin resistance and improve glycemic control. For instance, Nieuwenhuis-Ruifrok et al. (2013) showed that metformin significantly reduced insulin resistance in women with PCOS.
• Metformin was found to lower the risk of major adverse cardiovascular events in people who had metabolic syndrome, according to a study that was conducted by Rajagopal et al. (2018). The study focused on people who had the metabolic syndrome.
• Like myoinositol, metformin may also have side effects, such as gastrointestinal disturbances,
Now lets look at the mechanism of action and efficacy metformin and myoinositol:
1) Mechanism of Action:
A. Metformin: Metformin primarily works by reducing glucose production in the liver, increasing insulin sensitivity in peripheral tissues, and improving glucose uptake by cells.
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B. Myoinositol: Myoinositol is involved in insulin signalling and acts as a second messenger in insulin action. It is possible that it will improve insulin sensitivity and lead to improved glucose utilisation.
2. Its effectiveness in the treatment of polycystic ovary syndrome (PCOS):
a) Metformin: Metformin has been shown in a number of studies to improve menstrual regularity, induce ovulation, and reduce androgen levels in women with PCOS. In patients with polycystic ovary syndrome (PCOS), it is frequently prescribed to improve fertility outcomes.
b) Myoinositol: Research suggests that myoinositol supplementation improves menstrual regularity, ovulation, and hormonal profiles in women with PCOS. It may also enhance fertility outcomes. Some studies have reported comparable efficacy to metformin in improving PCOS symptoms.
3. Effect on metabolism
a) Metformin's Effects on Metabolism Metformin's effects on metabolism have been the subject of a significant amount of research. It reduces insulin resistance, improves glucose tolerance, and lowers fasting insulin levels. Some who have PCOS or metabolic disorders might also experience a slight reduction in their body mass as a side effect of this treatment.
b) Myoinositol: Myoinositol has shown promising effects in improving metabolic parameters such as insulin sensitivity, reducing insulin resistance, and improving lipid profiles. It may also have a positive impact on triglyceride levels and markers of cardiovascular health.
4. Tolerability and Side Effects:
a) Metformin: Although metformin is generally well tolerated, it has the potential to cause gastrointestinal side effects such as nausea, diarrhoea, and abdominal discomfort. These side effects can vary in severity among individuals.
b) Myoinositol: Myoinositol is considered safe and well-tolerated, with few reported side effects. It is generally considered to be a supplement that is well tolerated by the body.
5. Safety over the Long Term and the Optimal Dosage:
a) Metformin: Metformin is a drug that has been used to treat type 2 diabetes for a significant amount of time and has an extensive safety record. However, in some people, taking the drug for an extended period of time can lead to a lack of vitamin B12.
b) Myoinositol: Myoinositol is a naturally occurring substance and has been shown to be safe for short-term use. However, more research is needed to establish its long-term safety profile and optimal dosages.
Which is better for PCOS metformin or Myoinositol?
In short the we do not have much evidence to suggest which one is better .
It's important to note these opnions are my personal opinions and it is important to know that the choice between metformin and myoinositol should be based on individual needs, preferences, and consultation with a healthcare professional.
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Empty follicle syndrome (EFS) occurs when no eggs are collected during an IVF cycle, despite the presence of mature ovarian follicles. EFS is a rare condition and can be classified into two types: Genuine EFS and false EFS. Genuine: is failure to retrieve oocytes from mature follicles and Stimulation, good follicular development and Optimal hCG on day of OPU
False: Failure to retrieve oocytes in presence of low bHcg : Error in administration or bioavailability
The exact causes of EFS remain uncertain, but several factors have been proposed based on available data:
1. Insufficient ovarian stimulation: If ovaries aren't stimulated enough during IVF, mature eggs won't develop in the follicles.
2. Gonadotrophin use: In some cases, using only recombinant FSH for stimulation may result in a higher EFS rate, potentially concealing a Type 1 ovulation disorder.
3. Long-term oral contraceptive use: Starting ovarian stimulation immediately after stopping oral contraceptives can increase the risk of EFS.
4. Early luteinizing hormone (LH) release: Premature follicle maturation, caused by early LH release, has been associated with EFS.
5. Dysfunctional hypothalamic-pituitary-ovarian (HPO) axis: Disrupted hormone regulation in the HPO axis may hinder follicle development and maturation.
6. Ovulation trigger failure: HCG and analogue triggers have 1-3% failure rates. Trigger failure is more likely in women with low or high BMI.
7. Oocyte maturation arrest: Genetic or metabolic disorders can cause oocytes to stop developing normally, leading to EFS.
8. Technical difficulties during oocyte retrieval, such as improper follicle puncture or aspiration.
9. Timing of follicle aspiration: Aspirating follicles too early or too late can result in EFS.
10. Problems with the oocyte's zona pellucida, either structural or functional, can hinder its release during retrieval.
11. In some cases, the underlying cause of EFS remains unknown (idiopathic EFS).
Treatment options for EFS depend on the cause:
• Baseline FSH check
• Address weight issues and associated risks for low or high BMI
• Wait 2-3 months after stopping long-term oral contraceptives before starting stimulation
• Stimulate for more than 11 days
• Delay trigger until follicles reach 20 mm
Additional strategies include:
1. Adjusting the ovarian stimulation protocol by changing the type or dose of gonadotropins or GnRH analogue used.
2. Monitoring LH levels during stimulation to detect premature luteinization and modify the protocol accordingly.
3. Optimizing the timing of hCG administration for oocyte maturation, and potentially extending the period between the trigger and egg retrieval.
4. Ensuring proper follicle aspiration technique to reduce technical errors.
5. Increasing the hCG trigger dose in cases of high BMI.
6. Using a double-trigger protocol with both hCG and a GnRH agonist for complete oocyte maturation.
7. Considering donor eggs for patients with multiple failed IVF cycles due to EFS.
These suggestions represent a combination of evidence-based recommendations and personal practice.
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Sperm DNA Fragmentation
review of Paper
Journal of Reproductive Biology and Endocrinology, Szabo et al. 2023. Risk Factors Contributing to Increased Sperm DNA Fragmentation: A Comprehensive Review and Meta-analysis.
The main focus of the article is on the different risk factors linked to high sperm DNA fragmentation (SDF) and how they affect male fertility.
Fragmentation of sperm DNA and its risk factors
The systematic review found that many things, like a varicocele, poor glucose tolerance, testicular tumours, smoking, pollution, and paternal age over 50, can cause SDF to rise.
A spinal cord injury, using heroin, having chronic prostatitis, or having had an orchidopexy are also major risk factors for SDF.
There are dose-dependent effects on SDF from smoking, drinking alcohol, and having a high body mass index (BMI).
• Age had a bigger effect on SDF for people who were 50 years old or older.
How does age affect the way sperm DNA breaks up?
The meta-analysis found that age has a big effect on SDF, and that effect gets worse after age 50. Between men under 50 and men over 50, the average difference in SDF was 12.58 percent (CI: 7.31–17.86). This finding suggests that sperm DNA may break up more as men age, which could affect their ability to have children. But the exact links between age and SDF are still not clear, so more research is needed to figure out how they work together.
Fragmentation of sperm DNA and its role in infertility
SDF shows how many sperm have damaged DNA and has been linked to men not being able to have children. High SDF is linked to lower chances of getting pregnant naturally, more failed attempts at assisted reproduction, and miscarriages. DNA integrity is needed for fertilisation and normal embryo development. Studies have shown that infertile men have more damaged DNA in their sperm than fertile men.
So, SDF has become a very important part of figuring out a man's fertility. Its inclusion in international guidelines as a test based on evidence shows how important it is in clinical practise. Finding potentially changeable risk factors for high SDF could lead to more effective and cost-efficient ways to improve fertility, like making changes to your lifestyle.
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The precise mechanism by which injury enhances pregnancy rates is not well-understood, and current data on endometrial injury are insufficient to recommend routine use of this method. Further studies are required to determine if endometrial injury should be offered to patients to improve pregnancy rates
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The Gudi Triangle: Understanding ovarian reserve
The use of this triangle is to simplify the explanation of the ovarian reserve and its use in clinical practice. We are well aware of AMH is being a marker for ovarian reserve which comes from the small pre-antral, pre-antral and the small antral follicles. The antral follicle count is a visible indicator of the ovarian reserve and relevant to stimulation. Whilst the AMH also tells us about the inhibitory control of the follicles, the antral follicles tell us the response of the follicles to hormonal changes.
In the figure the bottom half of the triangle is indicated by the pre-antral follicles which predominantly secrete AMH. The middle part of the triangle is by the antral follicles which are divided into the large antral follicles and the small antral follicles. These antral follicles which are more receptive to stimulation and will respond to hormonal stimulation. Finally in the top of the triangle is the role that the ovary fulfils which is to have a dominant follicle.
The follicles move from the pre-antral zone to the small and finally to a large antral follcile . There is evidence that this is a continuous phenomena with the antral follicle counts changing. At the same time there is an invisible loss from the small Preantral and the pre-antral follicles indicated by the decline in AMH . Thus the AMH declines first as the woman starts ageing.
At the site of the antral follicles ,the small antral follicles are more likely to go into atresia or be recruited at a later part of the cycle. Large antral follicles have less inhibited control of AMH and are more likely to respond to stimulation. Follicles that go into atresia at this stage we call is visible atresia.
Thus by reviewing the antral follicle count and measuring follicle counts of more than 4 mm and those which are less than 4 mm we can divide the antral follicle into smaller the last both of which respond differently to stimulation. The AMH tells us to a large extent about the inhibitory response of the ovary and how easy or difficult stimulation would be. Often for women it is the antral follicle'and the variations in the follicles that matters at stimulation rather than AMH.
It is important to note that age alone is the best indicator of quality while the antral follicle count and the AMH tell us more about quantity.
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FertilityEducation is a comprehensive online educational platform dedicated to disseminating evidence-based medicine and fostering meaningful discussions about complex fertility-related issues on a global scale. With a team of highly skilled and experienced consultant physicians based in London, the site is committed to promoting best practices in reproductive medicine, ensuring that the information provided is firmly grounded in scientific research and clinical expertise.
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17 December 2016