The purpose of this post is to help answer some of the frequent questions couples have about improving their chances after a failed IVF. Many couples will have a baby from their first or second IVF cycle, which (obviously) suggests that IVF is all they need. Not getting pregnant after 2 or 3 IVFs or getting pregnant but repeatedly miscarrying should start to inform the doctor that there is something else that needs to be addressed.
Step 1 – Make sure you have all the information available
You want to know:
exactly which drugs you were on, what doses and for how long
what your ovaries (and uterus) looked like at baseline – just before you started your IVF, how many antral follicles were there on each ovary and was your lining nice and thin
what your basic hormonal profile (FSH, LH, estrodial, prolactin, TSH, Free-T4) looked like on day 1-3 of your cycle recently
how many eggs were recovered
what the sperm analysis on egg collection day looked like
what percentage fertilization rate you got
how the embryos looked on day 2 (good embryos have 2-4 cells, be symmetrical and not fragmented)
how the embryos looked on day 3 (good embryos have 6-8 cells, are symmetrical and not fragmented).
how the embryos looked on day 5 (they should be blastocysts – ideally expanding or hatching blastocysts)
how your embryo transfer was reported (easy or difficult)
whether you had cramps on ET day or the next 2 days
whether you had any symptoms of immune reaction to implantation (e.g., flu-like symptoms, sore throat, joint pain, fever on day 8-12 post egg collection)
whether you got any implantation at all – e.g,. a positive pregnancy test that faded or an ectopic.
whether you bled before test day
Step 2 – Check whether the signs were favorable when you started your IVF last time
Your lining should have been thin e.g., 3mm, when you started stimulation.
If you had troublesome cysts on the long protocol at baseline, it may suggest that you would do better on a different protocol e.g., a short agonist flare. Similarly, if you tend towards short cycles (or a short follicular phase) and you had 1 or 2 follicles that developed far ahead of the rest and had to be sacrificed to let the others catch up (often a bad idea as the fastest follicles may contain the best quality eggs of the whole batch), you may do better on a long protocol rather than short.
If you had less than 2 antral follicles per ovary at baseline, particularly if you had a high day 3 FSH and/or a low AMH, this could either mean it was a bad month for you to try IVF if you normally see more follicles than this at baseline, or it could mean that your ovarian reserve is poor, and you might be just as well to use a natural cycle IVF (no stimulation) as a stimulated IVF, or perhaps ask your doc to check your DHEAS level to see if you are deficient in case DHEA supplementation for 3 months might help, or ask your doc to consider you for an estrogen priming protocol.
If you have already been diagnosed with endometriosis, some ladies retain quite high fertility, but others have significantly impaired fertility due to endometriosis associated inflammation. If you do not get implantation with your first cycle, your doc should be considering protocols to reduce inflammation for you e.g,. 1-3 months on the pill followed by a 5 day letrozole protocol.
Step 3 – Understand your ovarian response
Your clinic should be aiming for a good response e.g., 8-15 eggs but not more than this. If you had a very high ovarian response and/or OHSS or a huge number of follicles but not many eggs recovered, particularly if you had a baseline antral follicle count greater than 10 on each side, a high AMH and a poor egg quality, that suggests that you were probably overstimulated. Possibilities for reducing the risk of over stimulation next time are:
checking whether you are insulin resistant and asking for metformin if you are
reducing your weight to get your BMI into the range 20-25
adopting a strict low GI diet
pre-treatment with inositol may help
asking to use a pill priming protocol (where you go on the pill for 1-3 months before your cycle starts to calm your ovaries)
asking to use a short agonist flare protocol or a conversion protocol instead of a short antagonist or long protocol
reducing the amount of LH in your protocol (e.g., using more gonal F and less menopur), but bear in mind some LH will probably be needed particularly on a long protocol or on an antagonist protocol after the antagonist is started
reducing the overall dose of stims or using alternate day dosing e.g., 150iu and 75iu on alternate days
using prolonged coasting – giving fairly low dose stimms e.g., 150 iu and stopping it as soon at least 2 follicles have attained a mean diameter of 18-22mm (on ultrasound) and 50% of the remaining follicles have reached 14-16mm, and waiting (up to 5 days) until the blood estrodial level falls below 2,500pg/ml before giving the HCG trigger shot)
using cabergoline tablets (a drug which has been shown to reduce the severity of OHSS without damaging egg quality/pregnancy rates) to reduce the chance of OHSS – although, typically this does not reduce egg numbers or help egg quality
freezing all embryos and having a FET the following month – although this does not reduce egg numbers or help egg quality but it can help to avoid dangerous OHSS
If you had a poor response (less than 4 eggs recovered on a typical stimulation dose (e.g., 10 days of 300 IU), then there are strategies to try and optimize your chances here in the poor response section:
The aim is to improve response to get more eggs but not at the expense of reducing egg quality. Some interventions may reduce egg quality so they may not work for particular patients. Other interventions may not improve response, but might help the egg quality. Some clinics will not tailor their protocols well to individual patients, so if your own clinic are not ready to discuss tailoring your protocol after a poor response cycle, you might want to get at least 1 second opinion from a more specialist clinic. These are my suggestions to investigate and discuss with your clinic.
1) switching protocol
Numbers of eggs recovered tends to be higher on the long protocol for normal responders – but some ladies have sensitive ovaries that don’t ‘bounce back’ well after having down regulated for the long protocol – so they may respond better to a short protocol starting on a natural period. Additionally, some ladies experience better egg quality on a short protocol. Accordingly, if you have had no success on the long protocol, it would probably be worth switching to the short protocol and vice versa.
Some ladies’ egg quality improves if their ovaries are ‘rested’ by a month or more on the pill before they start IVF – but other ladies have ovaries that don’t ‘bounce back’ well after having been on the pill – in which case, they may benefit from either a natural period start to their IVF, or using the agonist/antagonist conversion protocol overlapping with the pill (you start a daily dose of agonist about 5 days before stopping the pill – then on about day 2 of your bleed you stop the agonist and start an antagonist at half dose along with your stims).
Some ladies experience better response on a flare protocol (a short protocol where you start agonist at about the same time as stims so that the agonist produces a ‘flare’ of your own FSH to add to the FSH in the stims) – but sometimes this is at the expense of reduced egg quality – so again, you would probably have to try it to find out whether it suits your body – although some clinics avoid using flare protocols for all ladies because of the flare protocol’s reputation for reducing egg quality (particularly in older ladies) and because the level of FSH that your body will experience on a flare protocol is unpredictable (the flare protocol relies on pushing your body to produce its own FSH as well as giving the FSH in the stimms). Clinics who rely on tailoring your FSH and LH level very carefully by monitoring your bloods and adjusting your doses to get your FSH and LH into a particular target zone (e.g., ARGC) are less likely to use the flare protocol because of its unpredictability, but clinics who try to keep the costs of meds down as low as possible, sometimes use flare protocols for all/most of their patients, especially for normal responders, because using your body to produce some of the FSH needed reduces the number of ampoules of stims that need to be paid for.
For poor responders who do ovulate naturally, and particularly for older poor responders, some docs believe that although the chance of pregnancy with IVF is never going to be as high as for a normal responder of the same age, it is not improved by using high doses of stimulation meds, and and that natural cycle IVF may give the same chance or better as conventional IVF. Their approach is to try 2 or 3 cycles of natural cycle IVF instead of challenging the ovaries with medication. This means taking no FSH or LH medication at all and aiming to monitor the natural development of follicles on ultrasound (often starting with a scan 4 days before ovulation is predicted – ovulation is often predicted to happen 14 days before you expect your period). A trigger shot of HCG is then taken about 3 days before ovulation and egg collection happens 3 days after ovulation with the aim of collecting only 1 or 2 eggs, with embryo transfer happening usually on day 2 after egg collection. The aim of the natural cycle approach is to be as gentle as possible to the ovaries and keep your hormone levels as normal as possible in the hope of getting the best possible egg quality.
2) switching stimulation meds
Stimulation drugs can be pure FSH (e.g., gonal F, puregon, follistim) or mixed FSH and LH (merional, menopur, pergoveris) and can be natural (derived from human urine e.g, menopur, merional) or synthetic (e.g, gonal F, pergoveris). Most docs agree that we need some LH for good follicle growth, but some think that too much LH can be detrimental to egg quality. So if you have previously had a poor response on the long protocol with pure FSH, you may get a better response if you switch to short protocol (where you have some natural LH remaining in your system) or a long protocol with some LH (all or part merional/menopur). Some docs prefer natural stimulation drugs because they have a reputation for being more ‘gentle’ on the ovaries and often cheaper, but others prefer the synthetics which have a reputation for being more ‘intense’ – but so far, studies haven’t shown natural or synthetic to be clearly better for all patients, so its probably a question of which meds your body responds to better.
3) Pretreatment with DHEA
Older ladies tend to have lower levels of DHEAS and a reduced ovarian response. Some studies suggest that, if DHEAS levels in the blood are proven to be low, then taking DHEA as a supplement can get the level back into the normal range which sometimes improves ovarian response after about 3-6 months. Therefore, if you have had one poor response cycle, you might want to ask your GP to run the following bloods (ideally on day 1-3 of your cycle): DHEAS, free testosterone, estrodial, SHBG, FSH, LH and prolactin. If your DHEAS is low and your testosterone and LH are not already high and your SHBG not already low, then you might want to discuss taking DHEA e.g,. 25mg micronised DHEAS from a reputable brand e.g., biovea, 3 times a day for 3 months before your IVF cycle. After the first month, you should repeat the blood test to check you haven’t under or overshot the normal ranges. You do not want to have excessive DHEAS, testosterone, LH or low SHBG as this might reduce your egg quality.
4) Estrogen priming protocols
Good response tends to be associated with relatively low FSH levels, which is why some clinics suggest that poor responders should wait for a month when your FSH is at its lowest on day 1-3 to do your IVF cycle. Taking estrogen will tend to suppress FSH, so some doctors think that priming your body with estrogen injections or skin patches for about 1 week before starting stims can help poor responder patients.
5) Increasing the dose of FSH
Increasing the dose of FSH can often help recruit more follicles so reduce the risk of poor response – but some studies suggest that higher doses may reduce egg quality. Accordingly, some docs are reluctant to use high doses for some or all patients – or where they do use high doses (doses more than 300 IU), they will use a step down approach – where the patient starts on the high dose but only for the first few days before stepping down to a lower dose. If on your last cycle, you used a particularly low dose of FSH for your age group (e.g,. 225IU or 150IU for age 35), and your response was poor, its reasonable for your clinic to suggest trying a higher dose e.g,. 450IU stepping down after 4 days to 300 IU, but I would be wary of docs whose only suggestion when faced with a poor responder patient is to give enormous doses of FSH (e.g, 600 IU) unless perhaps the patient is a young poor responder who is likely to have excellent egg quality, or to keep trying high doses after it has already failed for the same patient.
Some supplements are supposed to help with poor response. For example, estrogenic/estrogen-like supplements may help reduce your FSH, which may help improve your response (e.g., wheatgrass, spirulina). Other supplements or lifestyle changes may just help your body cope better with the demands on it which might improve your egg quality e.g., royal jelly, extra protein. It is bound to be more difficult for your body to produce good eggs if you are tired and under nourished.
7) Thyroid problems
Undiagnosed thyroid conditions can increase the risk of poor response. So you may want to see your GP and ask for TSH, FT4 and antithryoid antibodies to be tested for. Do not accept that the results are ok without seeing the actual numbers for yourself because the optimal range for your health that your GP will accept is wider than the range which seems to be optimum for trying to conceive. You want to aim to get your TSH around 1 and your FT4 into the top third of the normal range. If antithyroid antibodies are detected it means you are at higher risk for developing thyroid problems even if your hormone levels are normal now. Some studies suggest that your chances of pregnancy can be improved if antithyroid antibodies are treated with a small dose of thyroxine, blood thinners and steroids (see Thyroid).
8) Immune issues
If you are relatively young and are experiencing poor response suggesting diminished ovarian reserve without an obvious explanation, it could be that your ovaries are suffering from attack by anti-ovarian antibodies. These are difficult to test for, but they are associated with premature ovarian failure and poor response to IVF. Some studies suggest that taking immune meds e.g., steroids (see corticosteroids) may help to reduce antiovarian antibodies, which might help the chance of pregnancy. However, where response is diminished due to immune issues, it is difficult to know whether the situation is reversible without trying it – logically, though, younger ladies are more likely to have reversible problems.
9) You may not be ready to consider donor egg treatment, but be aware that it does exist, and if you are prepared to wait or can travel overseas, its not difficult to arrange, or particularly expensive compared to own egg treatment. Even if it is something that you could not think about until you have tried several different OE approaches and still been unsuccessful, at least know that it exists, and that its readily available until age 50. So even if OE never works, and adoption isn’t possible for you, with DE there is still a good chance of having a baby (e.g., 70% after 2 cycles of DE) for most ladies until age 50.
10) Some ladies respond badly to a synthetic HCG trigger shot e.g. ovitrelle and do much better on a natural trigger shot e.g. pregnyl, gonasi or profasi. You can often get clues about this if you had plenty of follicles but not many eggs recovered as the synthetic HCG sometimes leaves the eggs still ‘sticky’ and difficult to flush out of the follicles.
Step 4 – what does the mix of eggs tell you?
Increased success rates have been shown where the batch of eggs collected included at least 1 or 2 immature eggs. Where there were no immature eggs, it may be a sign that stimulation was continued for too long and many of the eggs may be atresic (over mature). Immature eggs can sometimes be fertilisable by IVF but not by ICSI. So if there are sufficient sperm, it may be worth asking for IVF to be attempted on any immature eggs even if the main plan is to ICSI.
The embryologist should be able to give you some information about the apparent quality of the eggs prior to fertilization and should note, for example, if the eggs appear blotchy or have a thickened shell (zona). Those can be signs of reduced quality.
If the number of eggs recovered appears low compared to the number of follicles that were apparent before egg collection, that can indicate:
1) the doctor was unable to reach one of the ovaries e.g., due to adhesions/scarring which have pulled the ovaries out of reach, or due to the patient being very overweight.
2) there may have been premature ovulation before egg collection – this can be confirmed by taking a blood test for progesterone on egg collection day – if your p4 has moved above baseline before EC you know that you ovulated too early – a protocol including antagonist (cetrotide or orgalutran) or indomethacin (a very cheap drug that decreases some of the processes necessary to allow a follicle to rupture e.g., prostaglandin release) may help to prevent premature ovulation
3) the trigger shot may not have been taken late or the dose insufficient for the patient so the eggs have not fully released from the follicle. Its not unheard of for the patient to forget to take the trigger shot altogether.
Step 5 – understanding fertilization rate and the influence of sperm factors
If you had a fertilization rate of 75% most embryologists would regard that as good. Fertilization rates are often lower with ICSI e.g., 60%, partly because the sperm quality tends to be reduced but also because not all eggs survive the ICSI injection process and some may not be mature enough for ICSI. Fertilization rates of 50% are probably borderline and fertilization rates below 50% are usually regarded as poor.
If your IVF shows a poor fertilization rate, a good embryologist should be able to give some indication of why this was the case:
– the egg quality may have been noticeably poor – e.g., thickened zona, blotchy eggs, eggs that disintegrated when they were injected for ICSI – the options depend on the suspected reason for the reduced egg quality
– the eggs were mainly immature(stimulation may not have been carried out for long enough or the trigger shot was an insufficient dose) or over-mature (atresic – stimulation carried out for too long)
– in IVF, the sperm failed to bind to the egg – suggesting antisperm antibodies or a defect in the sperm – the next step may to do ICSI next time but it may also be helpful to run a test for antisperm antibodies (although if the semen has high viscosity or fails to liquify, this will mean that antisperm antibodies are very likely), and a test for sperm DNA fragmentation.
– the embryologist may have other reasons to suspect the sperm quality – e.g., the embryologist had trouble locating enough normal looking sperm for ICSI.
– bacterial contamination may be suspected – and the semen and embryo culture can sometimes be tested for this.
On a donor egg cycle, if the donor is proven and has had good results on previous cycles, if fertilization (or embryo development) is poor, that would suggest a significant problem with the sperm.
Many doctors put all the emphasis on egg quality and ignore sperm quality. If you have more than 3 IVF failures, even if the egg quality is suspect, it makes sense to not ignore sperm quality. In any case, if sperm parameters are less than ideal, or there is agluttination/failure to liquidise, testing for infections (e.g. chlamydia/mycoplasma/ureaplasma) makes sense – this can be done by semen culture, but some clinics prefer to test the female partner as they feel it is more reliable. Its better to determine whether there is a specific bacteria that can be targeted with appropriate antibiotics, but even if there is not, some clinics will suggest a 30 day course of 100mg doxycycline twice a day together with a course of high dose antioxidants (e.g., vitamin E and vitamin C) then retesting the sperm parameters (and DNA fragmentation) after 60 days. If there is a significant improvement, e.g., 200% improvement, that would normally suggest that an infection was contributing to the sperm problem.
Studies have also suggested that DNA fragmentation rates can be improved by frequent ejaculation (once a day) for at least 5 consecutive days (preferably longer) before egg collection – the theory being that getting rid of older sperm will get rid of the most dna damaged sperm).
In some cases, the male partner may have a history of viral infection.g, herpes which can contribute to inflammation and reduce sperm quality. Where that is suspected, some doctors will suggest a course of antivirals (e.g., 500mg valaciclovir twice a day for 21 days).
For egg quality: consider antioxidant pretreatment e.g., resveratrol and/or pycnogenol and/or lycopene pretreatment (also antioxidant diets e.g., those with lots of red/orange/green veg, wheatgrass, spirulina, beetroot powder etc), melatonin, inositol or alpha lipoic acid (mainly for PCOS sufferers),
3 months DHEA pretreatment (but only if the blood level of DHEAS is low and not if there is a high LH:FSH ratio, low SHBG, high testosterone, high antral follicle counts or PCOS),
consider assisted hatching if the zona (shells) are thickened,
high protein/low GI diet,
limiting LH (by using only/mainly pure FSH until day 4 of stims, and then using a limited dose of LH per day – e.g., using mainly gonal-F, puregon or follistim with either menopur or luveris to add LH) and by using long protocol or a short protocol with a half dose of antagonist which starts on day 1 of stims.
shortening the stimulation and not sacrificing the dominant (and probably best quality) follicles in order to allow the rest of the batch to catch up may reduce the number of eggs recovered but give a benefit to egg quality.
Anti-inflammatory diet/supplements if elevated TNFa (inflammatory immune problems) appear to be involved e.g., omega 3 fish oil, tumeric, nettle, resveratrol, pycnogenol, cordyceps.
Natural cycle IVF or very low dose stimulation protocols are worth considering to maximize egg quality but are more problematic if the sperm quality is also poor because not all eggs survive the ICSI process.
Step 6 – understand embryo development
Good quality embryos tend to fertilize and divide according to a regular timescale. The day after egg collection they should show clear signs of fertilization. On day 2 they should have 2-4 cells, be symmetrical and not fragmented. On day 3 they should have 6-8 cells, be symmetrical and not fragmented. On day 4 they should be a morula (lump of cells like a mulberry) and by day 5 they should be a blastocyst, ideally expanding or even starting to hatch. Embryos that deviate from normal development by dividing too quickly or too slowly, showing asymmetry on day 2-3 or lots of fragments are less likely to give a healthy pregnancy.
Bear in mind, however, that just because an embryo looks perfect, it is not necessarily capable of making a healthy baby. For example, where the egg is excellent quality but the sperm dna is very poor, the egg may be able to compensate for the defective sperm allowing the embryo to reach blastocyst stage and even implant but still not manage to make a healthy pregnancy.
If embryos are low quality/slow to cleave/cleave too quickly, then its obvious to suspect the sperm or egg quality, and it is worth asking for a sperm DNA fragmentation test to determine whether the problem is more likely to be the sperm or the egg or both. Although, the embryologist should have some idea about the egg quality from their observations.
Step 7 Was the lining adequate?
A good lining is triple layered, even, fairly dark looking on ultrasound rather than pale and about 9mm-14mm. Some doctors will insist that a thinner lining is not a problem and point to the fact that they have seen pregnancies with linings of only 6mm, but studies consistently show that the chance of pregnancy is better with a lining of 9mm than a lining of 6mm, and it is likely that the patients who do get pregnant with a lining thickness of 6mm are luckily very fertile in other ways (e.g., extremely good embryo quality) which is compensating for the poor lining. If your lining was reported as being less than 9mm, your doctor should try to address this next time rather than dismissing it as not being a problem.
A thin lining may be due to:
hormonal issues (e.g., estrogen being too low – which can be improved with estrodial valearate supplements e.g., oral or vaginal progynova (cyclacur white pills), skin patches e.g., estrofem, or injections of estrodial valearate (available in the USA but not in many other countries).
compromised blood flow – which can be tested for directly using a doppler ultrasound of the uterine artery (to measure RI – resistance index and to look for something called ‘notching’ on the doppler which indicates reduced flow), or which can be suggested by clotting issues (see Thrombophilia below), or by increased immune activity e.g, elevated NK activity which could increase the likelihood of microscopic clotting in the uterine lining tissue. Compromised blood flow can be improved with clexane and, potentially with vasodilating medication like terbutaline, trental or vaginal viagra (sildenafinil). Vitamin e, L-arginine and selenium have also been shown to help lining growth.
endometritis (inflammation of the lining) – usually due to an infection e.g., chlamydia, mycoplasma, ureaplasma. Sometimes apparent from a hysteroscopy as a red, spotty ‘strawberry-like’ lining. Usually easy to treat with antibiotics although if the bacteria can be successfully identified (e.g., by taking a biopsy sample and culturing it, or potentially, using the greek menstrual blood tests, it may be easier to choose an appropriate antibiotic.
permanent damage to the endometrium after an STD, PID or pregnancy related infection (post-abortal or post-delivery endometritis) or damage caused by scarring after instrumentation e.g., a D&C. Such scarring (e.g., Asherman’s syndrome where scar tissue joins the uterine surfaces in a series of adhesions) is usually visible by hysteroscopy, but not always. Scar tissue can often be resected (cut away) in a surgical hysteroscopy but some ladies are prone to recurrence of the scar tissues after the surgery. Some surgeons leave ‘balloons’ or coils in the uterus temporarily after surgery for Ashermans’s to try and stop adhesions reforming. Most doctors will prescribe estrodial medication after uterine surgery to reduce the chance of adhesion formation.
new treatments like PBMC, GCSF or uterine HCG may help lining issues – particularly uterine GCSF at least 2 days before ET
treatments such as saline flush or endometrial scratches probably will not increase lining thickness but may help implantation generally.
sometimes a hysteroscopy with a mild D&C can help to re-invigorate the lining tissue so that it grows more evenly but not necessarily more thickly next time.
Thick linings are sometimes seen with PCOS or perhaps adenomyosis (experienced docs should be able to identify adenomyosis from the appearance of an ultrasound scan but inexperienced docs find this difficult) , or sometimes due to the presence of a cyst which is releasing hormones and preventing the normal drop in hormones. Providing a thick lining has a normal appearance on ultrasound (uniform, tri-laminar) and has been shed recently (bear in mind that if you are post menopausal or have down regulated, lining does not start to grow until you start estrogen medication so it is ‘fresh’ at the point of starting estrogen meds), they are not thought to cause a problem, but an old, thick, patchy lining needs to be shed and regrown to give a better chance at embryo transfer. Studies have shown a significantly reduced pregnancy rate where DE recipients have been kept on estrogen for more than 5 weeks prior to ET (showing the effect of an old lining).
Step 8 Clues from how your embryo transfer was reported and whether you had cramps after transfer
An easy transfer has been suggested in some studies to lead to a higher chance of pregnancy than a difficult transfer. For a future transfer, it may be necessary to plan to dilate the cervix or use a different catheter to make transfer easier.
Other studies have suggested that patients who report cramps after transfer have a reduced chance of pregnancy but this may be improved by allowing the uterus to settle after the catheter is inserted but before the embryo transfer or by using medication called tocolytic.
Step 9 – Clues about implantation
If you do not normally get spotting on a non-fertility cycle, but you get spotting on a fertility cycle, it may be a sign that you are getting implantation but not much further. Its very hard to narrow down the cause of implantation failure e.g., :
egg quality problems
sperm problems e.g, DNA fragmentation
male or female karotyping defects
infection e.g., mycoplasma/chlamydia/ureaplasma causing a hostile uterus
poor quality lining/anatomical problems in the uterus e.g., impaired bloodflow, scarring, adhesions, polyps, fibroids
elevated natural killer cells and or elevated inflammatory cytokines causing a hostile uterus
endometriosis or other inflammatory conditions causing a lack of beta3 integrin in the lining
thrombophilias causing poor blood flow to the lining
hormonal problems e.g., hypo or hyperthyroid, poorly controlled diabetes or progesterone problems
anti-ovarian, anti thryoid or anti hormonal antibodies causing problems with egg quality and/or implantation
Women who suffer from an immune reaction to implantation may experience symptoms, particularly flu-like symptoms, joint pains, fever, skin rashes, sore throat usually on about day 6-10 after egg collection. These can be signs of rising inflammatory cytokines and NK activity. However, its possible to suffer from immune related implantation failure without experiencing any symptoms. Where immune related implantation/pregnancy failure is suspected, you doctor may suggest checking:
level 1 tests that a GP can arrange: for thyroid (TSH, Free-T4 and antithyroid antibodies), for autoimmunes (ANA, rheumatoid arthritis/lupus screening), vitamin D deficiency, clotting screen (including antiphospholipid antibodies).
level 2 tests that are only available through specialist laboratories: Natural killer cell assay, TH1:TH2 cytokines, LAD/antipaternal antibodies, HLA-DQA matching, genetic thrombophilias (MTHFR, Factor II prothrombin, Factor V Leiden, PAI-1).
Bleeding heavily (not just spotting) before pregnancy test day whilst still on progesterone support can be a sign of abnormal progesterone absorption or abnormal progesterone metabolism. This often occurs in patients who have high levels of a class of cells called CD19+5+ which is often associated with anti-hormonal activity. For some unknown reason, but perhaps related to stimulation of the immune system, low levels of progesterone are typical in patients who have a history of chlamydia. The easiest way to treat the problem is to use a higher dose of progesterone from about 6-7 days post egg collection and many doctors feel that an injectable progesterone is a more reliable way of ensuring a high enough level of in the blood.
Step 10- What are the options if everything looked perfect?
Dealing with unexplained repeat implantation failure can be frustrating, but the first thing to do is to check whether any obvious investigations have been missed:
karyotyping for both partners to check for a major chromosomal anomaly – if karyotyping is abnormal, then the next step is to see a genetic counsellor to understand its implications for the chance of having a healthy baby and whether PGD techniques can help
level 1 tests that the GP can do: thyroid (TSH, Free-T4, antihyroid antibodies. The aim is for TSH to be about 0.9-2 and for FT4 to be in the high normal range. If antithyroid antibodies are elevated, studies suggest an improved chance with IVF on a protocol including steroids, thyroxine and blood thinners), vitamin D deficiency (fertility is reduced and the immune system will tend to be dysregulated if vitamin D levels are deficient, ANA (elevated ANA may often signal autoimmune related infertility which can often be addressed with steroids and blood thinners and sometimes intralipids) clotting tests including antiphospholipid antibodies (elevated APLAs can be addressed with blood thinners and steroids, other clotting problems can often be addressed with blood thinners).
Basic hormone profile: day 1-3 FSH, LH, Estrodial, Prolactin, SHBG, DHEAS. If FSH and/or estrodial is high, then reduced egg quality and ovarian response is expected, but pregnancy may still sometimes be achievable using a carefully chosen IVF protocol. If prolactin is high, the first step is a referrral to an endocrinologist to make sure there is no sinister cause, but otherwise, your doctor will normally prescribe prolactin lowering medication like bromocriptine or cabergoline. Some studies suggest that IVF success rates will not be severely affected by borderline untreated elevated prolactin, but the higher the prolactin, the more necessary it will be to treat. If LH is high and or SHBG is low, the mix of stimulation drugs may be crucial to keep LH levels low. If DHEAS is low, sometimes poor egg quality and/or poor ovarian response can be reversed by taking a course of DHEA for about 3 months.
Sperm DNA fragmentation test for the male partner. If sperm DNA fragmentation is higher than ideal, changes in lifestyle (healthy diet with lots of vegetables, omega 3 containing fish, nuts and seeds, avoiding smoking, drinking and some prescription medications like anti-depressants) may help. However, frequent ejaculation and a course of antibiotics and high dose antioxidants before a retest after 60 days may also be helpful. Some specialist andrologists will also compare semen samples taken 2 hours after a first ejaculation as this sometimes yields a sample with better quality sperm (but possibly at the expense of a reduced count).
Careful visual check of the uterus for physical anomalies – aquascan by an experienced doctor, 3D scan or hysteroscopy. If aquascan or 3D scan reveals scarring, septa, adhesions, polyps or fibroids some doctors will suggest immediate surgical removal. Others will be more conservative and insist that they have had patients with similar defects who have got pregnant. That attitude can be unhelpful for the patient with repeat implantation failure because just because another, particularly fertile, patient managed to get pregnant despite the defect does not mean that the less fertile patient will manage to achieve the same result without surgery. That said, before contemplating surgery, do your homework and make you speak to several happy patients of the proposed surgeon. A good surgeon will improve your chances but a bad surgery will only make your situation worse.
infection testing (usually more reliable for the female partner) for chlamydia, mycoplasma, ureaplasma etc – many doctors will dismiss this as pointless, other than the basic test for chlamydia by urine or vaginal swab – however a minority of doctors will attest to the fact that they deal with many patients who have repeatedly been failed by other clinics only to finally get pregnant once they were treated with antibiotics. The conventional thinking is that because antibiotics haven’t been shown to increase the overall pregnancy rate for IVF patients, then they are not helpful. However, that ignores the fact that the majority of IVF patients do get pregnant after 3 cycles. For the minority who do not manage to get pregnant within 3 cycles, antibiotics may have a disproportionate impact.
Level 2 testing:
for genetic thrombophilias (PAI-1, prothrombin II, Factor V Leiden, MTHFR) which can be easily treated using blood thinners (and sometimes high dose folic acid, B6 and B12) – see Thrombophilias in my immunes FAQ
for natural killer cell cytotoxicity and or natural killer cell ratios – which can be treated using different combinations of intralipids, steroids, clexane (and possibly humira and/or ivig) – see NK assay in my immunes FAQ
for TH1:TH2 cytokines – which can be treated mainly with steroids, antioxidants, intralipids and possibly IVIG and/or humira – see Cytokines in my immunes FAQ
for HLA DQA matching – which can be treated mainly with intralipids – see DQa in my immunes FAQ
for LAD/antipaternal antibodies – which can be treated mainly with LIT (or possibly IVIG)- see LAD in my immunes FAQ
Step 11 – Interventions your doctors may have neglected
The main intervention is a thorough investigation and a very carefully chosen protocol for your IVF:
e.g., for normal or high responders, with a normal or longer than average cycle length a short flare protocol or a conversion protocol taking care to limit the dose of LH for patients who already tend to high levels of LH or polycystic ovaries, or to introduce LH once antagonist is started
for patients with a short cycle length and particularly a short follicular phase, a long protocol (to reduce the risk of a dominant follicle developing early on an flare or antagonist protocol – taking care to ensure that sufficient LH is used to allow normal follicle development
for poor responders with a normal or longer than average cycle length – an antagonist or possibly a conversion protocol – taking care to introduce sufficient LH once the antagonist is started, or a natural cycle IVF with no stimulation drugs, or an estrogen priming protocol.
Other interventions that may improve implantation rates include:
use of a 5 day letrozole protocol for patients with mild/moderate endometriosis, hydrosalpinx or unexplained implantation failure – see the Endometriosis section of my immunes faq for more information on this new protocol which is increasingly being used in the USA
PBMC intrauterine infusion – mainly for unexplained implantation failure – see the PBMC section of my immunes faq for this new procedure which was developed in Japan and is being used in Ukraine, Japan, Austria and Greece
G-CSF injections (or uterine washes) – mainly for patients with immune related infertility/implantation failure or very thin lining that doesn’t respond to other treatments – another new protocol being used a lot in the USA, Germany and Italy – see G-CSF/neupogen in my immunes FAQ
Endometrial scratch at least 2 weeks before embryo transfer – mainly for unexplained implantation failure – increasingly being used in the UK – see Endometrial scratch in my immunes FAQ – clinics like serum do a deeper endometrial cut at least 4 weeks before ET.
Aquascan/saline wash 2-3 days before embryo transfer (or hysteroscopy at the start of the treatment cycle/end of previous cycle)- mainly for patients with unexplained implantation failure – used routinely by clinics like ARGC and by many other clinics
HCG intrauterine wash (e.g., 500 IU HCG) immediately before embryo transfer – mainly for patients with unexplained implantation failure – another new treatment ‘tweak’ tested in Turkey and now being adopted by clinics in the USA
HCG luteal phase support and lining preparation e.g., 5000 IU on trigger shot day for donor egg recipients (or on the appropriate day before FET), 1500 IU ‘top up’ every 2 days for 4 or more days – a treatment regime that has been used by clinics in the USA for many years – but a benefit has been particularly suggested for patients with immune problems and those who have low LH due to being on a long protocol or being post-menopausal.
empirical treatment with steroids and blood thinners (and possibly intralipids) where there is a suspicion of immune related implantation failure – see Treating empirically in my immunes FAQ.
extended down regulation e.g., 1-6 months on agonist prior to embryo transfer, particularly where there is a suspicion of multiple small fibroids, adenomyosis or endometriosis – but with own egg IVF this can make ovarian response very poor, so it is more helpful for DE or FET. For own egg IVF, there may be some benefit to taking the pill for 1-3 months beforehand.
empirical use of antibiotics, particularly where there is a suspicion of bacterial infection e.g,. a history of chlamydia infection. Some clinics think that, in difficult cases, it is necessary to continue antibiotics throughout the IVF treatment cycle and until about 7 weeks of pregnancy.
empirical use of antivirals (e.g., 21 days of valaciclovir 500mg twice a day starting at the beginning of stimulation/estrogen), particularly where there is a suspicion of recurrent viral activity e.g., herpes.
Interval double transfer/sequential transfer – i.e., transferring 1 or 2 embryos on day 3 and then another 1 or 2 on day 5. This is hedging your bets in case none of your embryos make it to blastocyst or in case you have an unusually short implantation window.
Have your docs missed anything in your medical history that might be relevant? e.g., if your tubes are blocked – have they checked for hydrosalpinges (fluid filled, swollen tubes) that may be causing a hostile uterine environment due to inflammation – have they considered whether the tubes might be blocked due to endometriosis (if so, consider a 5 day letrozole protocol) or infection (if so, consider testing for multiple infections e.g., using Serum’s locus medicus and life code 7 tests – see my serum file, they are easy to do by post).
if you have a family history of stroke, blood clots etc, have they checked you for thrombophilias.
if you have a family history of autoimmune disease, your risk of autoimmune problems might be higher, so it might be worth doing autoimmune tests or maybe treating empirically with steroids and clexane (see Treating empirically in my immunes FAQ).
if you have a history of infection (chlamydia etc), even though it may have been treated, some docs think that it can reactivate on implantation, so there are antibiotic protocols used by some doctors during IVF treatment early pregnancy.
if you have a history of viral infection (herpes, HPV, chickenpox, shingles, epstein barr etc), some docs think this can cause immune activation, so they use empirical treatment with 21 days of antivirals during IVF treatment.