We are often asked if covid-19 vaccine reduces female fertility and whilst there were no trials specifically done on pregnant women, there is some evidence in trials to draw conclusions and it is reassuring.
In the article below, Viki Male, Lecturer in Reproductive Immunology at Imperial College London looks at the data available across the key covid-19 vaccines and it is reassuring.
Viki Male says, “In fact, multiple strands of evidence tell us that COVID vaccines do not reduce fertility. Pregnant people were not included in the first round of trials, and participants were asked to avoid becoming pregnant, but nonetheless a number of people became pregnant by accident. The accidental pregnancies occurred equally across the vaccinated and the unvaccinated groups, which tells us that vaccines did not prevent pregnancy. The people who became pregnant have been followed closely, and have had normal pregnancies”
For the latest data by Viki Male, please visit @vikiLovesFACS.
We now have good UK data to show that pre implantation genetic screening by embryo biopsy, in women over the age of 35 years, improves the live birth rates and reduces the number of attempts taken to obtain live birth.
This study, published in Journal of Assisted Reproduction and Genetics on November 12th 2021, examines the live birth and other outcomes reported with and without preimplantation genetic testing for aneuploidy (PGT-A) in the United Kingdom (UK). A total of 2464 PGT-A outcomes were reviewed.
See the article here.
Planned changes to the UK fertility legislation means that frozen sperm, eggs and embryos will be able to be stored for up to 55 years, over five times the current storage period.
Read more about the planned changes here.
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 Piri antral 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.
The menstrual cycle is divided into the follicular phase followed by ovulation and the luteal phase. The stimulation of ovaries in IVF is carried out usually in the follicular phase. The old concept is that follicles are recruited in the beginning of the cycle and ovulation occurs in the middle of the cycle. Though a large number of follicles start being recruited in the early part of the cycle and hence stimulation in the beginning of the period is considered to be normal.
There is evidence from cancer patients where stimulation is done randomly and also from research where follicles seem to be recruited at different times. There is some evidence that some women recruit follicles in the luteal phase better than in the follicular phase. Please also note that the recruitment window (that is where follicles can be recruited) is longer and wider in the luteal phase is increasing the possibility of recruiting more follicles.
It has been proved reasonably well that egg quality does not worsen whether you stimulate in the follicle or phase and luteal phase. This gives an option of better stimulating protocols which will allow for a better response and possibly more eggs and embryos. Any luteal phase stimulation or random stimulation necessitates freezing of embryos.
We are delighted that RCOG has made and statement regarding covid-19 vaccination and fertility in response to the myths that have been circulating recently.
Dr Edward Morris, President at the Royal College of Obstetricians and Gynaecologists, said: “We want to reassure women that there is no evidence to suggest that Covid-19 vaccines will affect fertility. Claims of any effect of Covid-19 vaccination on fertility are speculative and not supported by any data.:
Click here to read the full statement.
The Anti-Mullerian hormone is often regarded as a test which looks at the quality of eggs. Infact there is increasing evidence that AMH may not be a quality of eggs, but more a quality of numbers of small pre-antral follicles (small eggs in the ovary).
In earlier studies in the United States, the level of AMH did not prevent women from getting pregnant naturally. It seemed to be all age dependent. Age tends to be the most important factor. AMH does tell us about the number of eggs which remain, and its decline may tell us about how the ovaries’ eggs have started to decline. Other than that, except at very low levels, it does not seem to tell us hugely about what quality of eggs would be available.
There is no doubt that in IVF you require more numbers, and a low AMH may limit the number of eggs that may be available for IVF. A study published in 2019 in the RBM online looked at live birth rates in modified natural IVF, with women with very low AMH levels; 638 cycles were evaluated and there was no doubt that there was a weak correlation of AMH with live birth rates. Thus in this study, they used a modified natural cycle, where they added a small amount of FSH injections, an antagonist was added to block ovulation, and Indomethacin was given to lower the chance of eggs being released.
They looked at the live birth rates per cycle and it was between 11.6 per cent for a very low AMH to 17 per cent for a high AMH, and with a normal AMH it was 12.6 per cent. Per transfer again, chances of pregnancy remain very much stable. Cancellation rates were almost similar in all the three cycles, thus while AMH concentrations were a reliable marker of mild and natural IVF, its role in achieving a pregnancy in a natural cycle is limited and at present we feel that it is still very early to label women with a very low AMH as being infertile and having a lower chance of pregnancy, while pregnancy seems to be age-related. Some women tend to have a slightly better antral follicular count and may stand a better chance of pregnancy.
Progesterone is the main drug and hormone that in fact supports pregnancy. Its role in IVF is to support the second stage of pregnancy where the embryos are implanted, and in frozen cycles, as well as the donor cycles, progesterone becomes the main hormone that supports pregnancy.
There has been a huge debate whether progesterone has to be used as a vaginal preparation or injectable format. Multiple studies have been published, some indicating there is no difference in this treatment, while others indicate that the injections may be better.
A study was done when the progesterone was used in oocyte donation cases. There was some evidence showing lower progesterone levels at the time of transfer in oocyte donation cycles concerned with higher miscarriage rates, so in these cases, women who received oocytes were given either vaginal progesterone, and if they were pregnant, they were given an injectable weekly progesterone which is not available in the UK. Later on there was another group that was given weekly progesterone along with vaginal progesterone after embryo transfer, and in fact what was seen is that if you gave intramuscular throughout from embryo transfer, the live birth rates were the maximum, and in fact if you did not give any intramuscular progesterone, the live birth rates dropped to less than 16 per cent, while when you gave progesterone when HCG was positive, the live birth rate went up to 24 per cent.
Thus the evidence came up from this study that if you were to give injectable progesterone, the rate of miscarriage would drop as well as the chance of having a live birth rate was much better. It is likely that women having egg donation may suffer from prolonged hormonal deficiency, and in fact progesterone may decrease the uterine contractions. Thus progesterone may give us a much better chance of pregnancy, and giving injectable progesterone may increase the same progesterone levels and have a better impact.
Those of FSH and the level of the ovarian reserve marker AMH have an impact on oocyte quality. It is important to realise that egg reserve is measured in two ways, the AMH test, which to a large extent tells us about the ovarian resistance as well as tells us how many small follicles are present and which can be detected, and the antral follicular count, which tells us about the immediate recruitment of the follicles. IVF depends on stimulation of these antral follicles in order to get eggs.
Often, we manage to get a good stimulation of two follicles though in about ten to 20 per cent of cases, we see that the response to stimulation is variable and is not what we expect. There are studies that investigate the dose of FSH of the stimulating hormone as well as the oocyte quality, and a study published in Fertility and Sterility 2017 looked at various groups of patients; those who had a very low AMH, those who had a normal AMH and those who had a very high AMH. The study looked at the varying doses of medication which were given. Surprisingly the higher the AMH, the higher amount of drugs may be needed to stimulate the ovary, and this is in fact right, though with the high AMH, quite often a mild stimulation works. There are cases in which the follicles refuse to budge and may not be stimulated.
On the other hand, there is increasing evidence that if the ovarian reserve is low and AMH level is low, in those cases, giving a high dose of medications in fact goes against the recruitment of the follicles and they are not able to grow. This study does give us an idea that it is very important to look at the AMH, to understand what the AMH means and not have a finality attached to it. A low AMH to a large extent tells us that the ovarian reserve may be on the lower side, but does not tell us about quality, and in those cases often it’s a mild stimulation that works better, while in some cases of polycystic ovaries where the AMH is high, mild doses may not work, and thus trying to fine tune these areas are more likely to give us a much better response.
Ovum donation (OD) is a significant and important treat-ment option, not only for older women (as more than half of women aged over 45 years undergoing in vitro fertili-sation (IVF) treatment will use donor oocytes), but also for younger women. Reasons for women using donor ovum are many and include primary ovarian failure, surgi- cal oophorectomy, after radiotherapy or chemotherapy, poor oocyte quality, multiple failures of IVF, genetic disorders, Turners syndrome and advanced maternal age. Modern society where child bearing is delayed will only see this method becoming more prevalent.
Obstetric complications with IVF pregnancies are well documented. However, until recently OD had not previously been investigated as a separate subtype of this. It could be postulated that there may be more complications with OD pregnancies as the embryo is immunologically different to the mother. The subsequent allograft reactions can cause problems with placental development and function leading to pathol- ogy. Initial studies investigating OD pregnancies were inadequate due to small sample size and inappropriate control groups. Studies specifically comparing to spontaneous pregnancies alone are not suitable when we already know that IVF in itself increases the risk to both mother and baby. Recent research has optimised the control group by using women undergoing IVF with autologous ovum. Ovum donation has now been shown to be an independent risk factor for hypertensive disease in pregnancy, post-partum haemorrhage and increased risk of caesarean section. Neonatal outcomes are less clear-cut, although there is some evidence to suggest there is increased risk of small for gestational age babies and preterm delivery. It is now clear that OD pregnancies are higher risk than IVF pregnancies with autologous ovum and they should be treated as such. Women with ovum donation pregnancies should have obstetric-led care, in a unit which has ready access to both blood transfusion and cell salvage. Future research should investigate how to reduce the risk of ovum donation to these women.
If you are considering ovum donation, discuss the risks and complications with your fertility expert of for further information please contact Fertility Plus.
Ovulation is triggered mainly by two types of medications; HCG, which is available as Ovidrel, Gonasi or Pregnyl and Suprecur which is an analogue trigger. Both triggers act in different ways. The HCG trigger mimics the LH hormone (the hormone that starts the process of ovulation). When we look at the efficacy of this, often in IVF, we use an analogue trigger to lower the incidence of ovarian hyperstimulation syndrome. Though when we use this trigger, we know that freezing of embryos gives us a much better pregnancy rate, while using HCG gives a much better pregnancy rate during a fresh cycle.
Often it is asked, what if we give this during an intrauterine insemination cycle and use a Suprecur trigger when a woman gets more than three or four follicles? A study published in Fertility and Sterility in 2017 looked at randomising women who were given the analogue trigger which is Suprecur, and doing IUI along with an HCG trigger, and what that demonstrated is that even when nature was used to its best by doing IUI, with an HCG trigger the pregnancy rates rose to a significant 32 per cent, while it dramatically dropped to less than ten per cent in an agonist trigger. Thus there is good evidence now coming up in cases of stimulation of the ovaries in an intrauterine insemination cycle, where it is better to have a low stimulation, getting between one and three follicles and to use an HCG trigger.
The Pill is one of the main contraceptives used in the western world, it has been used for almost 40 years and has been extremely successful in delaying pregnancy. We have managed to get more evidence about the long term and short term aspect of the Pill on the ovarian reserve.
The ovarian reserve is the sum total of eggs which are present in the ovary and which can be recruited. It is a test that looks at numbers, and the anti-Mullerian hormone is one of the tests that can give us an idea of the number of small eggs that are left in the ovary. In a study which was published in Gynaecology magazine in 2015, it looked at the effect of long term hormonal contraception. For almost a year 145 women were seen, those were on the oral contraceptive Pill, the oestrogen and progesterone combined, for a mean period of around 11 years. AMH was collected after a year of stopping the Pill. What it did show was that 44 women had never used the oral contraceptive Pill, and when they had a look at it after a year, there was no difference between the ovarian reserve of those who were on the Pill for a long period and those who were not on the Pill for a long period or not taking the Pill at all.
This gives us a much better idea; it tells us that after a year of being Pill free, there is no difference between the number of follicles which have been generated and can be measured in an ovary which was exposed to the Pill for a long time and that which has not been exposed to the Pill. Also it tells us that the Pill is not protective; it does not protect the ovarian reserve and it does not improve the chance of pregnancy once you have been off it. Age tends to be the most important factor that looks at success, and thus with an advancing age, the quality of eggs also tends to go down.
This was a paper which was published in Human Reproduction Update 2011 where it looked at multiple studies. Ten studies were evaluated, and it was suggested that though aspirin may thin the blood and may help the chances in some cases of miscarriage, it does not improve pregnancy rates.
In 1997 was a first study to come out which suggested that aspirin may improve chances of pregnancy. Recent studies have indicated that they do not improve the blood flow in IVF patients, and also do not improve pregnancy rates. There is some evidence that they may lower the chance of getting pre-eclampsia in pregnancy and thus its use in pregnancy is continued.
The recommendations based on international evidence -based guideline for the assessment and management of polycystic ovary syndrome 2018 (1)
PCOS creates an insulin resistant state and can have significant metabolic effects. There is a huge amount of information of decreasing weight and its impact of reducing the symptoms and the biochemical aspects of PCOS. What is less know is whether dietary interventions are effective for improving weight loss, metabolic, fertility and emotional wellbeing. Whether specific dietary composition in lifestyle intervention is successful is controversial though it is marketed extensively.
Having reviewed the recent evidence which reviewed outcomes from a high protein diet to a high carbohydrate diet no evidence was found for the majority of anthropometric, metabolic, fertility and emotional well being; ie. the type of diet was not found to be effective in these studies. However it was found that regardless of the type of diet, diet aimed at reducing weight was of benefit to women with PCOS. Two large systematic reviews showed that there was no benefit with a specific diet and hormone level changes as well as insulin changes did not predict response . It was noted that weight loss was possible and patient complaint with low fat diet and reduced energy diets, though adding different micronutrient content seemed unjustified (2,3).
Is metformin alone, or in combination, effective for management of PCOS?
Metformin is a low cost, readily available medication that has been extensively used as an insulin sensitiser for over seven decades in DM2 and for several decades in PCOS. Insulin resistance is documented on clamp studies in 75% of lean women and 95% of overweight women and addressing this has underpinned the use of metformin in PCOS. Metformin is currently widely used by women with PCOS, yet the efficacy of metformin in terms of improving clinical outcomes remains uncertain. Side effects do cause concern, and metformin use in PCOS is generally off label.
In PCOS, evidence indicates that metformin is effective overall in improving weight but I suspect that this is mainly due to the side effects of metformin; nausea, vomiting and diarrhoea!
We know that AMH is a test that tells us more about the ovarian reserve and we also know that AMH declines as age advances, because it looks at the small follicles in the ovaries, but there are other factors which also have an impact on AMH.
When we come to the basics, the AMH is produced by granulosa cells, they are small cells of small and pre-antral follicles. The quantity of AMH also corresponds to the pool of these follicles. In a study published in the Reproductive Biology and Endocrinology in 2013, evaluated what happens to AMH during pregnancy; this was a study done on 554 women. What was noticed is that the AMH levels continued to drop during pregnancy and the levels significantly dropped as the pregnancies progressed. Once delivery took place there was a further drop to AMH. This was quite often age-related. Younger women saw a more dramatic drop, while older women did not see a much more dramatic drop, which is probably due to them having a low AMH.
When you look at the implication of this treatment it is important to realise that women who come in for treatment for their second baby just after they have had a delivery should be asked to wait for a couple of months until their egg reserve starts recovering, and this is something we learn from the study, not to rush into another treatment.
There is inadequate evidence to make a recommendation about the use of metformin for irregular menstrual cycles. Any efficacy in regularising menstruation usually takes at least 5 months. Weight loss has proved more efficient than metformin in restoring menstrual regularity.
The latest PCOS guidelines make the following recommendations regarding the use of metformin for non-conceptional indications:
We don’t often think that religion and fertility are connected, but for some patients undergoing fertility treatments consideration of the attitudes that their religion has towards assisted conception can be significant. The post below focuses on catholicism and fertility and is an extract from the paper “Religious attitudes to gamete donation” (Roy Homburg, Fatima Husain, Anil Gudi, Mark Brincat and Amit Shah), published in the European Journal of Obstetrics & Gynecology and Reproductive Biology.
The Catholic Church has a long tradition of pronouncements on family issues and particularly on the place of children within a family.
The original Church Fathers differentiated between conception and the entry of the soul that made a human being a person. This distinction was muddied with the discovery of DNA and whether it was the ‘new DNA’ or other reasons the shift occurred whereby human life was decreed as starting from conception.
The Catholic Church has a central authority in the person of the Pope who in certain matters is aided by the College of Cardinals and Bishops. From time to time documents are promulgated that are expected to be enforced throughout the world. There is teaching, which is subject to interpretation and which allows more flexibility. On matters of doctrine there is Dogma, which cannot be altered and has to be adhered to. Reproductive technology falls with the remit of teaching.
The Catholic Church is always conscious of suffering, and has always tried to help and protect the most vulnerable in society. Its
‘Option for the poor’ is a modern reflection of that teaching that has remained consistent. So of course the Catholic Church empathizes greatly with the plight of the infertile couple, particularly since the Catholic Church is family orientated, with the family being the basic building block. The Church does not allow divorce, intending to give greater stability to the family unit, and encourages the procreation of children (Go forth and multiply), so that it has strict teaching on, say, contraception. The central dilemma in the reproductive technology debate is who is the ‘poorest’ for whom the preferential option should be made. In the mind of the senior prelates and fundamental teaching, this is the embryo, whose human life started at conception and who is defenceless. It is this equation with a human life, from conception, that has led to what many regard as the rigorous and difficult position on reproductive technology that the Church has taken. It is the quality of life of a child produced with reproductive technology that is therefore debated, and the inevitable loss of numerous embryos regardless of in what condition they are lost. These are ‘’wasted” according to the strict parameters, in achieving a single successful outcome. Of course, as science develops it is increasingly obvious that if we were to compare like with like, far more embryos are lost, once again in whatever condition, in normal unprotected sexual intercourse in a fertile couple where some 60 to 70% of embryos are chromosomally bizarre and will not implant. Furthermore, of those that do implant some 20–25% will miscarry.
It is the inefficiency of reproductive technology that is one of the major problems.
The other issue is the use of gametes, or embryos, or indeed a uterus as a commodity and not as a gift of nature i.e. a gift from God. Thus oocyte donation and sperm donation are rejected because children born from such procedures will not have the reassurance of being brought up with a known and certain identity of their father and their mother.
Surrogacy is regarded with disdain since it is felt that this constitutes the exploitation of the poor and the under privileged either economically or psychologically. Of course the issue of mothers and sisters or friends volunteering has to be debated further but in general, apart from the crisis in identity, it is the protection from exploitation of the under privileged that is also taken into consideration. Thus sperm donors, oocyte donors, and surrogacy are seen as areas where the under privileged need to be protected from exploitation by the wealthier more powerful members of society.
One of the major problems is the so called quality control of PGS, or various form of PGD and is abhorred. The selection of the ‘perfect’ is Anathema since nobody who is born or conceived is to be disposed of. The church accepts imperfection with love and neither blames God nor the parents for such an event, as is made clear in the Gospels.
Donum Vitae the key document (1987) that deals with this subject speaks of “the right of every person to be conceived and to be born within marriage and from marriage”. The techniques are thus seen as dehumanising.
Finally consideration is made once again on the exploitation and with the commercialization of the couple undergoing treatment. As long as the success rate continues to be so (relatively) poor and the expense of resources so disproportionately large, a religion like the Catholic Church, concerned with the wellbeing of such a diverse multinational and multi ethnic community all over the world, has to have serious misgivings. The Church’s largest population are deprived and underprivileged so the elements of social justice come into the equation, and this includes the protection from possible exploitation, once more of the poor and vulnerable. The perceived vulnerable are the infertile couple and deserve protection.
Catholics have debated this issue continuously and dissected reproductive technologies to their core. The above constitutes genuine misgivings, if not a horror of certain technologies that bring not life, as is the practitioner’s intention, but the opposite. It is up to those involved in the field to argue eloquently, with intelligence and not in a dismissive and arrogant way and for a common language to be found.
Also this is a challenge to carry on proceeding with the development of science such that the ideal fertility treatment, even through reproductive technologies, will be found that will be more efficient, less wasteful and safer, both for the individuals involved and for the babies delivered. Reproductive technologies have done well, but the Catholic Church demands that in the treatment of infertility, practitioners do better, much better.
Ovulation is triggered mainly by two types of medications. One is HCG, which is available as Ovidrel or Gonasi or Pregnyl, and other is Suprecur, which is an analogue trigger.
Both act in different ways. The HCG trigger mimics the LH hormone (the hormone that starts the process of ovulation). When we look at the efficacy of this, often in IVF, we use an analogue trigger to lower the incidence of ovarian hyperstimulation syndrome. Though when we use this trigger, we know that freezing of embryos gives us a much better pregnancy rate, while using HCG gives a much better pregnancy rate during a fresh cycle.
Often it is asked, what if we give this during an intrauterine insemination cycle and use a Suprecur trigger when a woman gets more than three or four follicles. A study published in Fertility and Sterility in 2017 looked at randomising women who were given the analogue trigger which is Suprecur, and doing IUI along with an HCG trigger, and what that demonstrated is that even when nature was used to its best by doing IUI, with an HCG trigger the pregnancy rates rose to a significant 32 per cent, while it dramatically dropped to less than ten per cent in an antagonist trigger, thus there is good evidence now coming up in cases of stimulation of the ovaries in an intrauterine insemination cycle, it is better to have a low stimulation, getting between one and three follicles and to use an HCG trigger.
Luteal phase defect essentially is when the second phase of a cycle after ovulation is not supported well. This second phase depends on the corpus luteum, from where the egg has been released, to start secreting progesterone and it is this progesterone that supports the endometrium (lining of the womb).
There are cases in which a few days after ovulation there is a slight bleeding or spotting of blood that tends to occur, and this can slowly result in a period. To a certain extent this signifies a defect in the luteal phase. It is in fact extremely difficult to diagnose since its diagnosis requires a histopathological, a biopsy, evidence which is very difficult to obtain. Thus to a large extent it is what we observe from the evidence from how the treatment is carried out.
Luteal phase defect can be endometrial which means the defect lies in the progesterone activity in the endometrium or the defect could lie in the corpus luteum where the secretion is inadequate which may reflect on the quality of egg.
Both tend to mean very much the same. Often it is the quality of the egg that is released which may also determine what is left behind and thus supporting the endometrium, but sometimes the secretion of hormone is adequate and the progesterone effect on the lining of the womb, the endometrium, is not adequate.
There are different ways to treat luteal phase defects, one of the simplest is to add a small amount of HCG, the pregnancy hormone, a few days after ovulation, which helps to sustain and prolong the life of the corpus luteum. This is what a pregnancy tends to do. Pregnancy generally prolongs the life of the corpus luteum and thus allows for the corpus luteum to continue to work. By mimicking this, you can often extend the life of the corpus luteum and in a large number of cases prevent the spotting. Another treatment option is to add progesterone, a high dose of progesterone given after ovulation may also enable the support of the endometrium.
Ultimately, there is no fixed treatment and to a large extent the decision is made on a case by case basis depending on how the response is.
Unexplained infertility is where we do not find any cause of infertility, this is often after undertaking tubal tests, reviewing ovarian reserve, sperm is extensively seen and there are no fibroids or endometriosis as seen by a laparoscopy. In these cases this is known as unexplained infertility.
Often women are asked to follow IVF as a treatment of unexplained infertility. However, it is important to realise that IVF is an aggressive treatment involving surgical procedure where eggs are collected, and thus rather than rushing into IVF, it is reasonable enough to understand whether IUI may be an alternative treatment which would give us very good results.
In a study done at the Homerton Fertility Centre and published in Fertility and Sterility, IVF versus intrauterine insemination (IUI) was compared in a randomised control trial; 407 women were given three cycles of IUI with FSH injections or one cycle of IVF. Studies indicated that as long as there were between one and three follicles in the IUI cycle and IUI being performed over 24 hours later, the success rates suggested that the live birth rate in three cycles of IUI approached 26 per cent, which is exceptionally good and comparable to a cycle of IVF.
This is one of the questions we are often asked; whether IUI, intrauterine insemination, can challenge IVF. One of the reasons why IUI fails is because it aims towards minimising the number of follicles grown. It is important to know for which conditions we are doing IUI. The two main conditions where IUI seems to work very well is in unexplained infertility and in male factor infertility where the sperm counts are mildly low.
Change the drugs: the drugs that are used are either Clomiphene, Letrozole or HMG, and there is very good evidence that FSH injections which we give at Fertility Plus, give a much better success rate to intrauterine insemination.
Increase the number of follicles: it is common sense to realise that the more follicles or possibly eggs that you have will in fact give a better chance of fertilisation and thereby pregnancy, and that is something which we aim to look for, though this will slightly increase the chance of twins.
Timing: the timing of IUI generally should be just before ovulation and 24 hours after, and some doctors believe they can do it at 36 hours, but the accepted timing is between 24 and 36 hours.
Continue to have sex: it is also recommended that to continue to improve the chances the couple Also continue to have sex. This allows them to supplement and improve the chances of pregnancy.
Sperm: lastly often if there is a poor sperm count, the chances of pregnancy are reduced, and thus we have to think about a slightly new technique which is that of a consecutive ejaculate, and that is something where the man produces once again within 30 minutes, and some reports would suggest that there is a slightly better chance of pregnancy.
Endometriosis affects about ten per cent of women in the reproductive age group and between 20 to 25 per cent of women who have painful periods seem to have endometriosis.
A significant proportion of women who come to a fertility clinic also have endometriosis and have ovarian cysts in the form of endometriomas. In these cases, laparoscopy is the best treatment for this, and laparoscopy where we open the cyst (endometrioma), strip the cyst wall, gives better pregnancy rates, lowers the chance of recurrence and pain.
The question “does it also reduce ovarian reserve?” is often asked. AMH is a test that is done to check ovarian reserve. In a study which was done in Serbia, 54 patients in early follicular phase had an AMH test done and then had surgery. Of the cysts removed, they were opened, the cysts were stripped away and endometriosis treated. 37 of these had endometriomas at one side and 17 had bilateral endometriosis. The AMH test was done six months and 12 months later. There was almost a significant drop of AMH from 3.3 to 1.4 nano ml/l in six months and then 1.72. There were also bilateral endometriomas which were treated, there was a continual dramatic decline to very low levels from 2.55 to 0.98 (plus or minus the variables).
This evidence clearly indicates that endometriomas, the surgical stripping of endometriomas and coagulation leads to unwanted and inevitable damage to the ovarian reserve, more so with bilateral endometriomas.
If you are concerned about endometriosis and fertility, contact your GP or fertility specialist.
We don’t often think that religion and fertility are connected, but for some patients undergoing fertility treatments consideration of the attitudes that their religion has towards assisted conception can be significant. The post below focuses on judaism and fertility and is an extract from the paper “Religious attitudes to gamete donation”.
‘Be fruitful and multiply and fill the earth’ (Genesis 1:28) was the first commandment given to Adam after he was created. Similarly ‘He did not create the world to be desolate but rather inhabited’ (Isaiah 45:18) is a further basis for the importance of fertility for orthodox Jews. Rachel, the matriarch, declared to Jacob,’ Give me children, otherwise I am dead’ (Genesis 30:1). Indeed, these may account for the very liberal laws regarding infertility treatment in Israel,
Unlike secular Jews, orthodox Jews have some limitations regarding reproduction. Orthodox women are not allowed to have sexual contact with their husbands during menstruation and for seven days after the bleeding stops, after which they take the ritual bath and become ‘clean’ again. For the majority of women, this strictly kept law is not a problem but for those with a short cycle in whom ovulation occurs before the ritual bath, pregnancy is obviously out of the question. The only way round this situation is to delay ovulation which has been done using estrogens, clomifene and even GnRH agonists. The irony is that this law was designed to encourage fertility and ‘save’ the sperm until the fertile window.
Artificial insemination with donor sperm is generally frowned upon. Although not regarded as adultery, it is generally discour- aged. Egg donation is generally rejected outright although it is condoned by some if the husband consents. It is the question of who is the mother according to Jewish law which has created a fascinating philosophical discussion, as yet unanswered.
Interpretation of biblical writings and Jewish law into 21stcentury reproductive technology is attempting to keep up with the pace of progress. An account of these interpretations is made all the more complicated by the fact that the Jewish religion today, in addition to orthodox Judaism, has Conservative, Reform and Liberal branches. Furthermore, the state of Israel has laws which bind its, mainly Jewish, population. The following is an attempt to relate to the diversity of opinion on donor gametes within the Jewish religion.
When the husband’s sperm and the wife’s eggs are used, there is general rabbinical agreement that in-vitro fertilization (IVF) is permissible in accordance with Jewish law (halacha).
There are some caveats involved in this agreement. The procurement of a sperm sample is problematical as’ spilling of seed in vain’ is prohibited. This is usually overcome as a sperm sample for the purposes of IVF is regarded as pro-creative and not wasted. Sampling semen for a laboratory examination is, however, inadmissible for the strictly orthodox. As this examination is such an essential part of the initial infertility investigations, semen may be obtained from the vagina or from a condom with a pin-pricked hole in it, both following normal sexual intercourse.
An almost obsessive demand for the establishment of paternity and lineage, assumed for a baby conceived naturally but not assumed in the IVF laboratory by orthodox Jewish couples, presents a problem. Despite the fact that the vast majority of IVF centres are meticulous in their identification of the sperm, eggs and embryos, strictly orthodox couples demand the presence of a trained observer in the laboratory to oversee the procedures and ensure that they are performed according to the halacha.
In orthodox Judaism, artificial insemination with the husband’s sperm is permissible if the wife cannot become pregnant in any other way. Regarding the use of donor sperm however, opinion is much more divided and it is generally frowned upon. Artificial
insemination by a donor is not thought of as adultery as no sexual relations are involved but is, nevertheless, unacceptable by the vast majority of rabbinical authorities.
The Conservative movement in Judaism, mainly based in the USA, have a slightly more liberal view on AID. They allow donor insemination while stipulating that the use of anonymous donors is strongly discouraged. Most Conservative rabbis prefer that non- Jewish donor sperm be used to prevent ‘adultery’ between a Jewish man and a Jewish woman and to prevent future genetic incest among the offspring of anonymous donors.
Reform Judaism has generally approved artificial insemination by a sperm donor. In all streams of Judaism, the sperm donor is regarded as the father so that the child would not, by Jewish law, be considered the child of the infertile husband.
It is interesting to note that in Jewish orthodox circles, a male (sperm) factor is easily the most prevalent cause of infertility. For infertile couples in these circles, it is surely very good news that the use of intra-cytoplasmic sperm injection (ICSI), an IVF procedure involving direct injection of a single sperm into the egg, is now producing such good results. The need to use donor sperm to resolve severe male infertility is consequently diminishing since the advent of ICSI.
In the orthodox Jewish community, the attitude on whether to permit egg donation is deeply divided. Some rabbis reject this procedure unequivocally while others condone the use of donor eggs if the recipient has her husband’s consent.
The fascinating question of who is the mother in the case of egg donation, the genetic (donor) or gestational/birth (recipient) mother, has unique relevance in the Jewish religion. The determination of who is a Jew depends on whether the mother is Jewish.
If both the genetic and gestational mother are Jewish then, although the question of who is the real mother is debatable, the Jewish identity is not in doubt. However, many infertile Jewish women receive eggs from non-Jewish donors. In this situation even the wisdom of Solomon would probably have a problem deciding whether the baby is regarded as Jewish or not. Other religions do not have the same problem whereas traditional Judaism places great emphasis of the religious status of the baby at birth. This also has an impact in adult life for orthodox Jews as, for example, having a bar-mitzvah or permission to marry.
It is, therefore, not surprising that the debate of who is regarded as the mother following egg donation has generated a good deal of heat, if not light. There are rabbis who consider that the genetic mother is the true mother and if the eggs have been donated by a non-Jewish woman, the more stringent of these contend that the baby should be ‘converted’ to Judaism. Others regard the gestational mother as the true mother and this is also the view of the Conservative stream. For the Reform Jews, this is not a problem as if either the mother or the father is Jewish then the child is regarded as Jewish. Finally, Israeli law categorically states that the gestational mother is the mother of a child born following egg donation for all intents and purposes.
From the wide divergence of opinion expressed within the Jewish religion, it seems clear that the scriptures cannot provide all the answers to the moral and ethical problems posed by the rapid advances in assisted reproductive technology. The opinions are necessarily based on interpretations of the written word which, for all the wisdom therein, could not possibly have anticipated the ‘science fiction’ age in which we live today. The fact that fertility is at the forefront of Jewish philosophy will ensure the continuation of the debates and will continue to provide a source of fascination for those inside and outside this religion.
For some individuals and couples undergoing fertility treatments, the consideration of their religious attitudes towards fertility can be significant. For fertility practitioners it’s important to be aware of these attitudes in order to have the most understanding of their patients. In this blog, an extract from a research article ‘Religious attitudes to gamete donation’, we explore the relationship between fertility and hinduism.
Children have always been important since time immemorial and the continuity of the family unit has been of major significance in Hindu culture. Indian mythology is full of stories about what couples have done in the past to overcome their problem of infertility. Hindu Religion has tried to understand the natural hurdles infertile couples may face to fulfil their social obligations and made alternatives available.
The following story of sage Agastya from the great Hindu epic Mahabharata (written 2000 years ago) tells us why Hindus are so obsessed with children. Besides social factors like ‘someone to take care of me in my old age’, it directs our attention to a profound religious demand for a child.
Each individual is bound by Dharma to produce one child who must perform the annual ceremony of Shraadha (offering oblations to ancestors). This child is a Dharma Putra. The Shraadha offerings enable the ancestors to nourish themselves in their abode – Pitr loka. Without a Dharma Putra to make that offering, ancestors suffer torture, hunger and thirst on Pitr Loka
Dharma is essentially duty that must be performed for the well- being of self and society. Failure to do so leads to social anarchy and cosmic chaos. Producing a child is one’s earthly duty and necessary
for maintaining the stability of society. One can only renounce the world after they had fulfilled all worldly duties.(Manusmriti 3:37)
When a man could not produce a child from his wife, he was given the benefit of the doubt and allowed to marry again, and again. If despite this, he failed to father a child, it confirmed his sterility. The Scriptures suggest that another man (in the same lineage) be invited to cohabit with the wives (with the permission of the husband). This practice is known as niyoga. (Bühler, George,1886).
In the Mahabharata, when king Vichitravirya dies, his mother invites the sage Vyasa to produce children through her widowed daughters-in-law. Children thus produced were called children of Vichitravirya (the legal father), not the children of Vyasa (the biological father). The donor is not allowed to give his name to the offspring conceived from his donated sperm. The children born from such an act would be children of the legal husband and retain rights of inheritance from the legal father
King Pandu could not have sexual intercourse with his wives. Since he could not father offspring for succession, he renounced the throne. Dharma demanded children. His senior wife Kunti quoted that Dharma permitted demi-gods to impregnate his wives to have children who would be known as the child of Pandu. Thus came the five warrior kings of the Mahabharata who were acclaimed to be the righteous and the heroes of India (CandrabalıTripat.hı, 2005).
In the Kathasaritsagar, a collection of stories written in the 11th century A.D., there is a story of a king who makes an offering of rice balls to his ancestors. As he is about to throw the offering in the river, three hands reach up – one of a farmer, one of a priest and one of a warrior. The oracles revealed,’ The farmer is the man who married your mother, the priest is the man who made your mother pregnant and the warrior is the man who took care of you.’ The king is advised to give the rice ball to the farmer because scriptures describe him as the true father. (Penzer, 1924),
Through many centuries, religious law allowed for donor insemination when approved by the couple and like today, the family name would continue and this would be accepted by society.
In the Bhagavata Purana, there is a story that suggests the practice of surrogate motherhood. King Kamsa imprisoned his sister Devaki and her husband Vasudeva because oracles had informed him that her child would be his killer. He killed six children of Devaki and Vasudeva. The Gods intervened and had her transfer the seventh foetus from the womb of Devaki to the womb of Rohini (Vasudeva’s other wife). A child conceived in one womb was incubated in and delivered through another womb.
Hindu mythology contains numerous incidents where sexual interactions serve as a non-sexual and often a sacred purpose.
From the many stories expressed in the Hindu texts, it is clear that the scriptures provide an indication to the moral and ethical problems faced by the rapid advances of infertility technology. There is no doubt that having a child is the forefront of a Hindu couple’s duty and the philosophies have given some evidence that different techniques may be tried to help the couple to conceive. Though ART was not known in ancient times, examples are cited demonstrating that the ancient sages understood the problems of infertile couples and justified treatments outside natural means of conception.
Folic acid is involved in gametogenesis, fertilisation and pregnancy, and thus may play an important role in human reproduction.
In the 1990s it was recommended that folic acid be given between a dose of 0.4 and 0.8 mg to prevent neural tube defects. There were some controversial studies in the mid-1990s that may have suggested that folic acid supplementation may increase spontaneous abortion. This was successfully challenged by other studies, and in the recent Cochrane review, based on three randomised control trials, suggested that folic acid in both doses of 0.8 mg and 0.4 mg in two studies, plus a multivitamin supplementation before and during pregnancy, did not increase abortion rates.
In another observational study called the Nurse Study 2 (NHS 2) suggested reduced spontaneous abortion risk among women using folic acid before or during early pregnancy particularly, and recommended that this be taken.
There is a lot of talk around vitamin D and pregnancy rates and outcomes but what exactly is known about the relationship between vitamin D and assisted reproduction? Here we look at the studies that have evaluated the effect.
Vitamin D Modulatory Process
It is well known that vitamin D receptors are distributed across reproductive systems including ovaries, uterus and endometrium. Furthermore it is known that vitamin D stimulates egg production, most follicular maturation and regulates successful implantation, and it may be involved in polycystic ovarian syndrome.
Vitamin D and Reproductive Outcomes
In animals there seems to be a strong association between reproductive outcomes with vitamin D. Women participating in the NHS 2 study, Nurse health study number 2, vitamin D was unrelated to infertility. Similarly it was not associated with either/or probability of conception in healthy Danish women or conception in less than one year among Italian women undergoing routine aneuploidy screening. Furthermore meta-analysis of 10630 pregnant women revealed no association between low vitamin D levels and miscarriage rates, though extremely low levels of less than 29 gram per ml were associated with increased risk of miscarriages in a small number of women.
Vitamin D and Assisted Conception Outcomes
Though vitamin D may give a positive benefit for reproductive outcomes, vitamin D on ART outcomes are inconsistent. In a large meta-analysis of 11 studies of women undergoing ART, it was found that women deficient in vitamin D levels had a higher probability of live birth, but no association with vitamin D with probability of miscarriage was noted. Similarly another study found in PCOS patients that vitamin D of great than 30 nanogram per ml was associated with lower live birth rates. This proved other studies which showed there was no association between vitamin D concentrations and the assisted conception outcomes. Furthermore two further randomised control trials did not improve pregnancy outcomes. Neither giving 50 thousand international units of vitamin D for six to eight weeks for deficient women, nor administering a megadose of 300 thousand in women with PCOS improves outcome.
In summary we could suggest that vitamin D can affect reproduction, though at present evidence is limited. Extremely low vitamin D levels are related to worse outcomes in ART.
The empty follicle, or not getting any eggs on an egg collection is one of the most distressing things that tends to happen. Does empty follicle syndrome occur, the answer is yes.
There are three types of empty follicle syndrome;
In a case presented in Human Reproduction they evaluated a woman who underwent nine cycles of IVF with HCG trigger. In the eighth cycle there were no eggs, in the ninth cycle an analogue trigger was given 40 hours before and a double trigger was done, and 16 eggs were obtained after eight cycles of IVF, thus signifying that sometimes changing the trigger significantly changes the outcome of pregnancy.
Studies among sub-fertile women suggest a variable outcome in women taking foliate supplementation on ART outcomes.
In small randomised control trials women who took folic acid 0.4 mg had 16 per cent higher probability of pregnancy compared to placebo. In addition, two studies, the MTHFR mutation (low MTHFR allele activity and low serum foliate levels) was associated with poor ovarian response, fewer oocytes and lower gonadotrope cell production. An ART study in Boston, the EARTH study, showed that consuming more than 0.8 mg foliate compared to consuming less than 0.4 of foliate before conception had a higher rate of pregnancy. This has also been challenged by other studies which show in three European studies that it did not show a benefit, but this study may be challenged that certain patients were excluded.
In summary we could say that folic acid supplementation before and during pregnancy is not associated with the risks of miscarriage, but may still improve the chances of women achieving and maintaining pregnancy.
In a study done in Human Reproduction in 2011, this question was answered to a meta analysis, is aspirin effective in women undergoing in vitro fertilisation? Aspirin has often been given to women undergoing IVF with the hope that it improves blood flow of the endometrium and allows the embryo to implant.
In the study ten studies were looked at in which aspirin was given and it confirmed that it did not improve blood flow in IVF patients and it did not improve pregnancy rates. There is some evidence that aspirin prevented the occurrence of preeclampsia during pregnancy, though the evidence is small. It is concluded that aspirin does not improve pregnancy rates in IVF and its routine prescription in IVF cycles is not good.
It is common practice to trigger ovulation at 18 mm size follicle. Surprisingly all this has been standardised, and all the evidence which has been obtained has been obtained on the basis of studies done in the 1980s and 1990s, however many of the studies were done on those of IVF rather than on Clomiphene or Letrozole.
In an analysis of 988 cycles published in Fertility and Sterility, in a retrospective analysis they looked at the best time to trigger ovulation, rather than triggering at 18 mm; triggering at 22 and 23 mm seemed to give the best chance of success as well as improving the endometrial lining. By waiting for the follicles to grow larger, the endometrial thickness varied and improved, thus it may be important to wait and trigger ovulation around a slightly later time so as to improve the chances of pregnancy.
We are often asked which is best; fresh or frozen embryo transfer. At Fertility Plus, we often favour frozen embryo transfers as this allows us to manage the timing better, but let’s understand a bit more about the evidence behind fresh and frozen transfers.
A large study published in a New England Journal of Medicine in January 2018 using women in China who did not have polycystic ovaries in their first IVF cycle between 20 and 35, had a stimulation and were given an HCG trigger. Of these women, 1077 had a frozen transfer and 1080 had a fresh transfer, results showed no difference between the live birth rates between fresh (50%) and frozen transfer (49%). The first trimester loss (miscarriage) was similar, though in a frozen cycle the second trimester loss was significantly lower at 1.5 per cent compared to 4.5 per cent fresh embryo transfer.
Whilst showing no significant difference between fresh and frozen in the case of women without polycystic ovaries, in the cases of polycystic ovaries freezing of embryos would significantly improve pregnancy rates.
The advantage of a frozen cycle is whereby the acute stage of hormonal treatments are phased out and embryo transfer is done at a much better time when the ovaries do not have to work extra, hence at Fertility Plus we generally favour frozen embryo transfer.
Sensationalist media sometimes even call it ‘the end of civilisation’ which is nothing more than scaremongering, but the question does remain …. “have sperm counts declined?”
This question has been a controversial question, and the first time it was mentioned was in 1992, where it was suggested that there is a genuine decline in sperm quality over the past 50 years. This controversy has progressed unabated and has never been answered due to the lack of proper studies which have been conducted.
The reason why it’s important is that sperm counts are linked to male fertility, and semen analysis may be the only accepted way of assessing, or rather being the first stance of assessing male infertility. There are reports that suggested the economic burden that male infertility gives. It is also known that these sperm counts are the cause of male infertility and also the cause of multiple environmental factors such as endocrine disrupting chemicals, pesticides, heat, lifestyle factors, diet, stress, smoking, body mass index, all may be responsible for a decline in sperm counts.
In one of the largest systematic reviews done, published in Human Reproduction Update in November 2017, a team looked at 2510 full articles and looked at a huge number of studies between 1973 and 2011. This statistical evaluation reported a significant decline in sperm counts between 1973 and 2011, driven by a 50 to 60 per cent decline among men unselected by fertility from northern Europe to America, Europe, Australia and New Zealand. The research also indicated that there is no evidence of levelling off which means of slowing down of that declining trend.
The causes which could be environmental or lifestyle in early childhood as well as in adult life, the endocrine disruption that comes in men from chemical exposures or maternal smoking during the critical times of male reproductive development, the exposure to pesticides that may have a role in adult life. The worrying factor is that we don’t know. At present, research is inadequate, but it is concerning that sperm counts are declining. A more robust long-term study is needed, and while this is on, it may be time to improve on how men look at health.
If you are considering starting a family it is worth the male partner doing the following:
If any medications are being taken they should be reviewed with a doctor.
As part of a patient’s treatment sometimes additional fertility procedures can be recommended; endometrial scratch is fertility procedure that we can recommend in certain cases, especially where there have been failed cycles. In this article, I explain endometrial scratch and the evidence supporting it.
Endometrial scratch is an additional fertility procedure where the endometrium (lining) is disturbed prior to an IVF cycle. This helps the embryo implant in the womb which is an essential part of fertilisation.
Before IVF, the womb lining is scratched with a small sterile plastic tube, which triggers the body to repair, releasing chemicals and hormones that make the womb lining more receptive to an embryo implanting.
There is reasonably good evidence that suggests that by doing an endometrial scratch prior to an IVF cycle or prior to embryo replacement success rates may be improved. This evidence now comes from previous two or more failed cycles where this intervention could be helpful.
There are no risks associated with endometrial scratch, so it is considered a safe procedure.
Endometrial scratch is still relatively new and we are unaware whether there may be an improvement in pregnancy rates if it is done before an intrauterine insemination cycle.
In one of the largest studies which was published in Fertility and Sterility in 2017, an analysis was done of 23 studies of a total of 1871 cycles in which the endometrial scratch was done in the cycle prior. The evidence suggested that a scratch may improve the chances of a pregnancy in an intrauterine insemination cycle.
Though doing this may seem better, its evidence is not as good as that in IVF. The studies also concluded that the evidence was not as robust as performed in the IVF studies, and thus this should be taken more cautiously.
The HFEA regard endometrial scratch as a procedure which consistently shows benefit however further evidence is needed and as such there is a large clinical trial underway in the UK called the Endometrial Scratch Trial.
Endometriosis is one of the most common diseases found in reproductive women, with a significant impact on quality of life as well as fertility. For a long time, we are not entirely certain if oocyte quality is affected by endometriosis. In one of the reviews of literature published in 2017 in the general ovarian research, the effect of endometriosis was discussed. It is known that endometriosis causes distortion of the pelvis and also may release inflammatory markers (cytokines). It’s also known that it may impair endometrial receptivity.
The impact of endometriosis could be on mitochondrial content (the battery of the cell), show granulation, which is the breakdown of cytoplasm, measure spindle abnormalities in the cell and also may harden the zona, the outer shell of the cell. It is known that women with endometriosis have an imbalance in oestrogen, seen in IVF. They have lower levels of oestrogen during the IVF cycle, and it seems that the progesterone requirements are also altered in an IVF cycle.
It is known that in women with endometriosis the eggs obtained have a hardening of the outer shell. There seem to be more immature than mature eggs, and also the spindle which is required to maintain the apparatus of the oocyte also seems to be altered in some cases of endometriosis. Mitochondria which are the batteries of the cell seem to be lower in endometriosis. In simple terms, is oocyte quality in endometriosis affected? Yes, there is a seven per cent more reduction in fertilisation, we get fewer eggs, fewer oocytes and less fertilisation.
The answer is no. Surgical intervention seems to have a negative impact on the ovary. Three to six months of long down regulation was suggested to improve pregnancy rates, but this has not been proved. There is some evidence that ICSI, rather than IVF, must be done to improve chances of fertilisation.