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.