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In vitro fertilisation
REVIEW
In vitro fertilisation
The basic infertility workup aims at identifying the causes contributing to difficulty in conceiving, and determining the prognosis for spontaneous treatment related conception. In addition, fertility clinics have a unique opportunity to optimize preconception health.
Abha Maheshwari
Abstract Infertility affects 1 in 7 couples. An etiological diagnosis is made to plan treatment. In a quarter no diagnosis can be established, hence a diagnosis of unexplained infertility is made. IF conception does not happen after an etiological diagnosis based treatment or unexplained infertility is diagnosed, in-vitro fertilisation (IVF) is the treatment of choice. Over last 4 decades IVF processes have evolved. There are better tests to predict ovarian response and a number of stimulations regimen to choose from. Better prediction means ovarian hyperstimulation can be predicted and minimised. Cryopreservation of gametes and embryos have become vert successful process, to the extent that policy of freeze all for all has been discussed. It is important that advances in this field are properly evaluated before being put in routine clinical practice for not only pregnancy rates but long term outcomes.
Assessment for contributing causes The investigations done to identify the causes contributing to infertility are to establish ovulation, assess semen analysis and tubal patency. Ovulation: ovulation is assessed by mid-luteal progesterone in regular menstrual cycles. In the presence of irregular menstrual cycles, it is important to do a basal hormonal profile to rule out any underlying hormonal disturbances which have implications for spontaneous as well as treatment-related conceptions. This includes hyperprolactinaemia, PCOS (polycystic ovarian syndrome) and late onset congenital adrenal hyperplasia. The basal hormonal profile should include serum TSH (thyroid stimulating hormone) FSH (follicle stimulating hormone), LH (luteinizing hormone), PRL (prolactin), testosterone and oestradiol
Keywords ICSI; infertility; IVF; pregnancy Semen analysis: semen analysis is an essential step in assessing a couple’s fertility. Results should be assessed against WHO reference values. This test only determines whether sperm are present, looking normal and moving. The positive predictive value of a semen analysis test for predicting pregnancy/nonpregnancy is poor unless there is severe oligozooasthenoteratospermia/azoospermia. Functional sperm tests and tests for sperm DNA fragmentation do not have proven value at present, so should only be done in a research setting
Introduction Infertility affects one in seven couples. Management approaches range from expectant management to ovulation induction, reproductive surgery and assisted conception. In vitro fertilisation (IVF) is the most effective infertility treatment, though not all couples need IVF. The first baby as a result of IVF was born in 1978. Since then there has been an exponential increase in the use of the technology with over 8 million babies born worldwide. The initial application of IVF was in women with blocked fallopian tubes, but over the years, indications have been modified and expanded. The technology has evolved with a number of significant advances in clinical and laboratory techniques and associated regulation.
Tubal patency: tubal patency was traditionally tested by X-Ray based hysterosalpingogram (HSG); however, better methods are now available avoiding radiation such as HyCoSy (hydrocontrast sono-salpingography). HyCoSy has the advantage of being done by the same team as at the fertility clinic, hence a follow up plan can be made at the same time, avoiding radiation and identifying any polyps/fibroids. If HyCoSy is inconclusive, or there are further findings that need treatment prior to IVF/other fertility treatments, a laparoscopy with or without hysteroscopy should be done There is no indication for doing either/both of these procedures routinely for all women undergoing fertility evaluations.
General infertility work up Infertility is defined as a failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse. Increasingly, it is recognized that the desire for a child is not restricted to heterosexual couples and the case mix in clinics reflects this, with increasing proportions of single women and same-sex couples seeking parenthood. The landscape of infertility clinics is changing, hence they should be called fertility clinics rather than infertility clinics. Among heterosexual couples there is a higher proportion of second relationships as well as those in which the partners are older than 35 years of age.
Assessments to optimize preconception health Men and women who attend fertility clinics are generally a young and healthy population who do not attend clinics/hospitals for other reasons. Fertility clinics have a unique opportunity to optimize their general health and provide preconception advice. Body Mass Index: ideal BMI is 18.5e24.9. There is evidence that miscarriage rate is increased both for spontaneous conception as well as treatment related conceptions when BMI is increased Higher BMI is associated with lower pregnancy rates in IVF as well as other fertility treatments.
Abha Maheshwari MBBS, MD, FRCOG Director and Person Responsible, Aberdeen Fertility Centre, Aberdeen Maternity Hospital, Aberdeen, UK. Conflicts of interest: none declared.
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REVIEW
to operate on endometrioma and other ovarian cysts should individualized based on size, access to remaining antral follicles, previous surgery and symptoms. This should be discussed in a multidisciplinary team meeting
Smoking: there is evidence that smoking affects the ovarian reserve (number and quality of eggs). Eggs are only formed once in a lifetime. Hence ovarian age of smokers is increased even if they were ex-smokers. Smoking also affects sperm and is associated with increased DNA fragmentation. There is reduction in IVF success rates when one partner is smoking, and further reduction if both partners are smoking
Ovarian reserve assessment: this can be done by using AFC or AMH or both. The purpose is to determine which stimulation regimen is best based on prediction of response. Both AFC and AMH are very good at predicting poor and hyper responders. This also helps in counselling couples/women
Thyroid: although, there are no recommendations that a thyroid function test should be done routinely, it is recommended by the American Thyroid Association that pre-IVF TSH should be <2.5 mu/l. It is clear that TSH >4 mu/l (i.e. subclinical hypothyroidism) should be treated preconception, but there is controversy for TSH levels between 2.5 and 4 mu/l. Recent evidence from large trials have suggested that presence of thyroid antibodies may affect the outcomes of IVF treatment; however, there is no evidence that giving thyroxine reduces that risk. Hence, it is suggested that there may be another mechanism by which antithyroid antibodies have an impact on the success rates
Endometrial scratching: the value of endometrial scratching is uncertain and it should not be offered routinely Blood borne virus screening: all couples undergoing IVF should have blood borne viral screening done. This is to identify any existing/past infections. According to legislation the gametes and embryos where there may be possibility of transmitting infections should be processed and stored separately. This includes HIV, hepatitis B (both surface antigen and core antibody) and hepatitis C
Rubella: Rubella immunity is determined by serology. However, screening test of rubella is no longer routine in the UK, and everyone is encouraged to have MMR (measles mumps, rubella) vaccination. This is a unique opportunity to immunize those who missed the vaccine
Indications for IVF IVF, though a long and invasive treatment, can be used for any cause of infertility – ovulatory, tubal, male or unexplained (Figure 1). There is an ongoing debate about how wide the indications for IVF should be. Proponents of IVF argue that it is an effective and safe treatment. The risk of ovarian hyperstimulation syndrome (OHSS) can be controlled with the use of preventative measures targeted through ovarian reserve testing. IVF gives the ability to select embryos, and single embryo transfer can be done to prevent multiple pregnancies. In addition, there are cost savings from not pursuing a full aetiological diagnosis which involves investigations and multiple hospital appointments. Opponents of IVF for all causes of infertility argue that it is expensive and invasive. A high proportion of patients will not need it if they are appropriately identified and treated. There are risks associated even with singleton pregnancies as a result of IVF as compared with those of spontaneous conceptions in terms of higher risk of pre-term delivery – small for gestational age babies, congenital anomalies, perinatal mortality, gestational diabetes and pregnancy induced hypertension. There are no head to head trials comparing clinical and cost effectiveness of IVF for all without aetiological diagnosis versus the current practice of step-wise use of IVF. At present, UK practice follows the model of aetiological diagnosis followed by an algorithmic use of IVF (Figure 1).
Assessment to determine prognosis Prognosis of spontaneous and treatment-related fertility is dependent on several factors, most important being age of female partner, ovarian reserve, duration of infertility and parity. Ovarian reserve refers to the number and quality of eggs. In addition to the age of the female partner, the two frequently used assessments are antral follicle count (AFC) which is ultrasound based and serum measurements of anti-Mullerian hormone (AMH). Both are equally effective in predicting hyperstimulation and poor response with the latest studies suggesting that AMH has a slight edge over AFC. The longer the duration of subfertility, the lower the chances of conception. This applies to spontaneous as well as IVF conception. Several prediction models exist across the world based on different datasets to determine a couple’s chances of spontaneous and treatment-related conceptions. They have moderate accuracy and can be used to advise women/couples of their chances. These models in an ideal world should be used to decide who, when and how to treat. However, at present the models are not sufficiently accurate to be used for this purpose. A lot of research is ongoing using data and artificial intelligence to move towards this.
IVF treatment
Pre IVF work up Ultrasound assessment: a pelvic ultrasound should always be done pre-IVF. This is to assess pelvic anatomy and identify abnormalities that need to be addressed prior to IVF. There is evidence that presence of hydrosalpinx halves the success rates, hence it should be removed, or interrupted to prevent hydrosalpinx fluid from accessing the endometrial cavity. The decision
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Once it is decided that IVF treatment is the appropriate way to treat the couple, the couple are counselled about the treatment. IVF involves several steps: stimulating the ovaries with gonadotrophin injections, retrieving oocytes by a surgical procedure, mixing eggs and sperm together to achieve fertilization and then growing embryos in the laboratory until they are ready to be transferred back to the uterus, or frozen for future use.
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REVIEW
Indications for IVF Wait for 2 years
Unexplained infertility
Conventional path based on NICE alogrithm
Investigations to determine etiological diagnosis – Ultrasound – Semen – HSG/HyCoSy – Laparoscopy – Progesterone
Superovulation + IUI
IVF
Wait for 3 years
IVF
Tubal surgery
IVF Wait for 1 year
IVF
Tubal factor
IVF
Male factor
IVF IVF
IUI
IVF
Gonadotrophins Anovulation
Clomiphene citrate
Laparoscopic ovarian diathermy
CC/ Gonadotrophins
IVF
Superovulation + IUI
IVF
Conservative treatment
IVF
Surgery
Endometriosis
Figure 1 Indications for IVF.
desensitization reduces the secretion of LH and FSH. GnRH agonists are commonly used in a ‘long’, starting in the middle of the luteal phase of the preceding menstrual cycle. They may also be started with gonadotropins (‘short’ protocol). GnRH antagonists competitively bind to GnRH receptors in the pituitary gland, blocking the release of LH and FSH. They are usually started on day 5 or 6 of gonadotrophin stimulation or when the leading follicle diameter is 14 mm, and continued throughout gonadotropin stimulation
Ovarian stimulation Multiple eggs are required for the process of IVF. In order to achieve this, ovaries are stimulated with external gonadotrophins. There are various aspects to stimulation regimens. Gondotrophins: there are various preparations available, providing Follicle Stimulating Hormone (FSH) and luteinizing hormone (LH) activity alone or in combination. Broadly speaking, these may be classified as recombinant or urinederived products (Table 1). Multiple trials have been published but no one preparation has been found to be better than the others
Monitoring of the ovarian response to stimulation: ovarian stimulation has to be well controlled as the aim is to develop multiple but not too many follicles. Research indicates that the cumulative success rate of IVF is higher with a higher number of eggs collected. This must be balanced against the risk of OHSS, which increases once the number of eggs crosses 20 Monitoring is done by ultrasound and/or oestradiol monitoring. There is a controversy about the value of oestradiol for monitoring cycles with a normal response. Ultrasound monitoring usually starts on the eighth day of stimulation and is repeated every 2e3 days, until the patient is ready for trigger and
Pituitary suppression: in addition to the gonadotrophins, pituitary suppression is used so that multiple follicular recruitment is possible without inducing an endogenous LH surge. This is done by countering the effect of endogenous gonadotropin releasing hormone (GnRH) through its agonists or antagonists. GnRH agonists interact with the GnRH receptor to produce a ‘flare’ response, followed by desensitization of the pituitary gland (by causing GnRH receptor downregulation) to GnRH. Pituitary
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REVIEW
All egg donors as well as those having fertility preservation should be given antagonist-based regimens as they are shorter and have a lower risk of OHSS.
Variety of ovarian stimulations options available (with permutation combinations from each column options) Gonadotrophins Type
Delivery
Dose increments
Practice points for ovarian stimulation Follicle Stimulating Hormone (FSH) Follitropin Alpha Follicle Stimulating Hormone (FSH) & Luteinizing Hormone (LH)
Recombinant Pre-filled Pen Follitropin Alpha
37.5 iu
Urinary Derived Highly purified human menopausal gonadotrophin (HMG) Biosimilar
75:75iu ratio or 150:150iu ratio
C
C
Multidose or single Vials of Powder and water for reconstitution
C
Pre filled syringe 150 iu/225 iu/ 300 iu prefilled syringes Single vials of 75 iu powder and water for reconstitution
Antagonists based regimens are shorter and have lower risk of OHSS Predicted hyper-responders, egg donors and those undergoing fertility preservation should be commenced on antagonist-based regimens and low dose gonadotrophins. GnRH agonists can only be given for ovulatory trigger if anantagonist is used for pituitary suppression.
Oocyte retrieval (‘egg collection’) Egg collection is the most invasive part of IVF. The majority of procedures are performed transvaginally, under ultrasound guidance. However, women with vaginal agenesis or ovaries that are displaced outside the pelvis may need laparoscopic egg collection. Egg collection is done 34e38 h after the ovulatory trigger to allow the oocyte to mature but to collect it before it is ovulated. The needle is passed through the vagina and follicles are punctured under ultrasound guidance, with fluid collected in test tubes. The fluid is then passed to embryologist who identifies the egg surrounded by cumulus cells (Figure 2), and removes it from the fluid. On average, eggs are retrieved from around 80% of the follicles seen on ultrasound. Although a very safe procedure, there are risks associated with egg collection such as infection and bleeding. There is no indication for giving routine antibiotics, unless the patient has a history of pelvic sepsis, hydrosalpinx or an endometrioma that is traversed by the needle.
Table 1
oocyte retrieval. Hence during a stimulation period of 2 weeks 3 e4 ultrasounds are needed until there are 2e3 follicles of 17e18 mm diameter. Ovulation trigger: once at least 2e3 follicles are present of 17 e18 mm diameter, the final ovulation trigger is given. Traditionally HCG was used for this, acting a surrogate for endogenous LH. However use of HCG is associated with a risk of ovarian hyperstimulation. An alternative approach in cycles using GnRH antagonist for pituitary suppression is to use a single dose of GnRH agonist as a trigger. This works by inducing an endogenous LH surge through its flare effect. The LH surge is sufficient to induce final maturation of the oocyte, but is not sufficient to produce adequate corpus luteum function. As a result, any embryos that are generated should be frozen for future use, or only transferred with added hormonal support In general, based on whether the patient is predicted to be a poor, normal or hyper-responder (as predicted by ovarian reserve test) one can follow the regimen given in Table 2. Apart from predicted hyper-responders, regimens should be chosen based on costs, local availability, patients and clinic preferences.
Laboratory processes Once eggs are removed from the follicular fluid, they are placed in specialized culture media. Not all oocytes that are obtained are mature. Some are at germinal vesicle stage or metaphase I. Sperm preparation: sperm is obtained on the day of egg collection, unless it has been frozen previously. Sperm is prepared to select the most motile sperms. Various techniques have been described to prepare sperm with no one better than other, hence every laboratory needs to use a validated technique with their processes
Preferences of ovarian stimulation regimens Prediction of response
Gonadotrophins
Dose (iu)
Pituitary suppression
Ovulatory trigger
Poor Normal Hyper responders Egg donors Fertility preservation
Any Any Any Any Any
300 150e225 150 150 150e225
Any Any Antagonist Antagonist Antagonist
HCG HCG GnRHagonist GnRHagonist GnRHagonist
Table 2
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REVIEW
uterine cavity), the endometrium is more receptive and embryo selection is better (not all embryos survive in culture to the blastocyst stage). This has led to increase in pregnancy rates per embryo transferred. A higher proportion of embryo transfers are now at blastocyst stage Embryos that develop into blastocyst by day 5 may be transferred or frozen for subsequent treatment. Those embryos that do not form a blastocyst until day 6 are best frozen, as the endometrium becomes asynchronous for implantation by that stage. They may be thawed later and transferred with success rates equal to a fresh embryo transfer. Use of time lapse: many clinics are using undisturbed culture systems, with time-lapse imaging to grow embryos. The undisturbed culture provides an advantage as strict conditions are maintained. Time-lapse imaging also allows the use of algorithms, which scientists can use to select embryos with the highest likelihood of implantation, and deselect those with an abnormal developmental pattern. However, there is no evidence that using such algorithms to pick the best embryos really leads to an increase in live birth rate Culture media used in a laboratory may be single-step or sequential. Single-step media are used throughout the culture period without changing, while sequential media require changing after 3 days. There is an increasing use of single-step media due to the increasing use of time-lapse systems.
Figure 2 A mature egg surrounded by cumulus cells.
Mixing sperm and eggs: sperm and eggs are mixed together by using standard technique of IVF or more invasive ICSI (intracytoplasmic sperm injection) IVF e in IVF prepared sperm are put around the eggecumulus complex and they are incubated overnight. In this process sperm are selected naturally. In addition, as eggs are within cumulus complex, it gives an opportunity for further maturation, in case some were at metaphase I stage. Insemination is done at 40 h post ovulatory trigger
Embryo transfer Embryo transfer is a simple process usually requiring no anaesthesia or analgesia. This is done under transabdominal ultrasound guidance. The outer embryo catheter is placed just beyond the internal os followed by the inner catheter loaded with an embryo. The tip of the inner catheter is placed 1e2 cm below fundus and the embryo is then expelled. Soft catheters are used for embryo transfers with an echogenic tip that is visible on ultrasound. There is no evidence that there is any requirement of antibiotics/bed rest after embryo transfer.
ICSI e ICSI was first used for male factor infertility, i.e. when sperm count is very poor/very few motile sperm are seen. It is also used in cases where there has been previous vasectomy or where there has been previous failure of fertilization using standard IVF. ICSI is done at 38e40 h post ovulatory trigger. In order to do ICSI, cumulus cells are removed from the eggs followed by injection of a single motile sperm into each mature egg. Only eggs that are at metaphase II stage can be injected. It is an invasive technique and has a 5% risk of damage to eggs; in addition, the selection of sperm is done by embryologists as opposed to natural selection as in IVF Although there is no evidence that ICSI leads to higher pregnancy rates for non-male factor infertility, the proportion of cases having ICSI is rising globally. Many scientists are using them for unexplained infertility or when there are small numbers of eggs. There have been attempts to use hyaluronate binding and high resolution microscopes to select sperm but none of them has proven in large randomized trials to be better than current morphological-based selection.
Frozen embryo transfer The ‘best’ embryo is chosen for the fresh embryo transfer. Any remaining embryos that appear to be of sufficiently good quality may be frozen. Frozen embryo can be used if fresh embryo transfer is not successful or for a sibling pregnancy if fresh embryo transfer was successful. Freezing used to be done by slow freezing but now most clinics prefer vitrification. Embryo survival rates with warming following vitrification are over 95%. Luteal support Luteal support is essential in IVF treatment where cycles have had external gonadotrophins. It is usually started on the day of egg collection and continued at least up until the day of a pregnancy test. Most clinics continue it until 7e8 completed weeks where as some continue it until 12 weeks. There is no evidence in the literature that continuation beyond the pregnancy test leads to an improved pregnancy rate. Progesterone given vaginally is the most commonly used luteal support. Those who cannot tolerate tablets can be given vaginal gel. Alternative routes for progesterone are subcutaneous, intramuscular and oral. There is no evidence that one is
Embryo Culture: approximately 60e80% of injected/inseminated eggs turn into embryos. These embryos are then cultured in specified conditions. In the early days of IVF, embryos were put back into the uterus 2 or 3 days after culture. With advances in culture conditions we are now able to grow embryos for much longer. This means that embryos can be cultured to day 5 or 6, i.e. blastocyst stage. It is considered that embryo transfer at blastocyst stage is better because it is more physiological (as this is the stage in natural conception when the embryo reaches the
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REVIEW
predicted by the above described risk factors. This is self-limiting once the effect of exogeneous HCG has disappeared. If it is diagnosed prior to embryo transfer, embryos should not be transferred and should be frozen for future use
better than others. There is no evidence that adding oestrogens to progesterone leads to an improvement in pregnancy rates. HCG is rarely used for luteal support, due to the risk of OHSS.
Complications e OHSS Late OHSS: this occurs 9 or more days after the trigger. This is usually due to endogenous HCG and occurs in those who are pregnant. Known risk factors are only poorly predictive of the risk of late OHSS, which is more likely to be severe and prolonged than the early form
Ovarian hyperstimulation (OHSS) is an iatrogenic complication of ovarian stimulation with exogenous gonadotropins. The pathophysiology involves ovarian enlargement and fluid shift from the vasculature into the third space. The clinical severity of OHSS can be classified as shown in Table 3.
Symptoms and management of OHSS Symptoms of OHSS are non-specific such as nausea, vomiting and abdominal discomfort. Hence, a high index of suspicion should be maintained for anyone having ovarian stimulation. Patient and doctor awareness are key. Alternative diagnoses should be considered in the presence of severe abdominal pain or fever, including: pelvic infection, complication of an ovarian cyst, intra-abdominal haemorrhage, ectopic pregnancy, appendicitis and gastroenteritis. Initial management should include clinical assessment and investigations to classify it as mild, moderate or severe (Table 3). Management is usually supportive. Specialists in reproductive medicine should be involved in care, as they are most likely to have the appropriate expertise and experience. Women with severe OHSS or those who have moderate OHSS but are finding it difficult to manage pain relief or fluid intake should be considered for hospital admission. The main aspects of care are fluid management, thromboprophylaxis and drainage of effusions. Intensive care colleagues should be involved if features of ‘critical’ OHSS are present.
Risk factors for OHSS The risk is higher in women who have: An antral follicle count (AFC) 20 Higher levels of anti-Mullerian hormone (AMH) Polycystic ovaries Younger women Lower BMI Higher number of medium-sized follicles during stimulation Higher oestradiol levels during the stimulation phase Use of hCG for luteal support (rather than progesterone) Previous OHSS Higher number of oocytes collected Achievement of pregnancy Types of OHSS Early OHSS: this occurs within 7e9 days after the triggering ovulation and is caused by exogenous HCG. This can be
Prevention of OHSS Various strategies have been used to prevent OHSS: Identification of appropriate cases based on tests of ovarian reserve Low dose stimulation for those predicted to be hyper responders GnRH agonists for ovulatory trigger instead of HCG; no HCG for dual trigger Planned freezing of all embryos. This would avoid late OHSS by avoiding pregnancy in the stimulated cycle.
Classification of OHSS Mild OHSS
Moderate OHSS
Severe OHSS
Critical OHSS
Abdominal bloating Mild abdominal pain Ovarian size usually <8 cma Moderate abdominal pain Nausea vomiting Ultrasound evidence of ascites Ovarian size usually 8e12 cma Clinical ascites (occasionally hydrothorax) Oliguria (<300 ml/day or <30 ml/h) Haemoconcentration Haematocrit >45% Hyponatraemia (sodium <135 mmol/l) Hypo-osmolality (osmolality <282 mOsm/kg) Hyperkalaemia (potassium >5 mmol/l) Hypoproteinaemia (serum albumin <35 g/l) Ovarian size usually >12 cma Tense ascites or large hydrothorax Haematocrit >55% WCC >25 000/ml Oligo/anuria Thromboembolism Acute respiratory distress syndrome (ARDS)
Policy of freeze all For those who are at risk of ovarian hyperstimulation, freezing of all embryos is associated with a reduced risk of OHSS, especially late OHSS which is difficult to predict. Clinical trials show that pregnancy rates of thawed frozen embryo transfers are similar to those of fresh embryo transfer. Hence it has been suggested that we should freeze all embryos and thaw and transfer them at a later date in the interests of safety, without reducing efficacy. Randomized trials have suggested that the pregnancy rates are 15% higher for a freeze-all policy for those predicted to be hyperresponders. However, no difference has been shown for normal responders. In addition, it has been shown that the risk of small for gestational age babies and preterm deliveries is reduced in
a
Ovarian size may not correlate with severity of OHSS in cases of assisted reproduction because of the effect of follicular aspiration.
Table 3
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thawed frozen embryo transfers when compared to fresh. However, thawed frozen embryo transfers are associated with higher risk of large for gestational age babies and increased risk of preeclampsia. Hence, there is an ongoing controversy about the value of freeze-all, other than for predicted high responders where it does appear to offer a significant benefit by abolishing the risk of late OHSS.
RCOG Guidance on OHSS- Green top guidance https://www.rcog. org.uk/en/guidelines-research-services/guidelines/gtg5/. Roque M, Haahr T, Geber S, Esteves SC, Humaidan P. Fresh versus elective frozen embryo transfer in IVF/ICSI cycles: a systematic review and meta-analysis of reproductive outcomes. Hum Reprod Update 2019 Jan 1; 25: 2e14. Maheshwari A, Bhide P, Pundir J, Bhattacharya S. Routine serum thyroid-stimulating hormone testing-optimizing pre-conception health or generating toxic knowledge?. Hum Reprod 2017 Sep 1; 32: 1779e85.
Pre-implantation genetic testing Pre-implantation genetic testing for aneuploidy (PGT-A) refers to testing embryos for genetic abnormality and replacing only an embryo that is chromosomally normal. When there is a known genetic abnormality in either/both parents it is called preimplantation genetic diagnosis (PGD). Trails show that the transfer of screened euploid embryos is associated with high success rates. However, the value of PGT-A has not been proven through randomized trials, and it should be kept in mind that this is a method of embryo selection rather than embryo improvement. Embryo biopsy is carried out on the trophectoderm at the blastocyst stage and carries a risk of embryo damage. Embryos need to be vitrified until the results of genetic testing are available. Further, the occurrence of mosaicism in blastocyst embryos poses a challenge to accurate diagnosis. As a result, PGT-A is not standard treatment at present. A
Practice points C
C
C
C
FURTHER READING HFEA webpage on add ons https://www.hfea.gov.uk/treatments/ explore-all-treatments/treatment-add-ons/. NICE fertility Guidance- CG156 https://www.nice.org.uk/guidance/ cg156.
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Indication of IVF are increasing, and it is now most frequently performed fertility treatment AMH and AFC are good predictors for poor and hyper response following ovarian stimulation There are no indications for
C
7
Doing endometrial scratching Using ICSI for non-male factor infertility Selecting sperm using high hyaluronidase binding Freezing all embryos for all Pre implantation Genetic testing for aneuploidy
A high index of suspicion should be maintained for OHSS for anyone undergoing ovarian stimulation. Preventive strategies should be adopted wherever possible. Involve IVF specialists Continuing luteal support beyond positive pregnancy test is not based on evidence
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In vitro fertilisation
The basic infertility workup aims at identifying the causes contributing to difficulty in conceiving, and determining the prognosis for spontaneous treatment related conception. In addition, fertility clinics have a unique opportunity to optimize preconception health.
Abha Maheshwari
Abstract Infertility affects 1 in 7 couples. An etiological diagnosis is made to plan treatment. In a quarter no diagnosis can be established, hence a diagnosis of unexplained infertility is made. IF conception does not happen after an etiological diagnosis based treatment or unexplained infertility is diagnosed, in-vitro fertilisation (IVF) is the treatment of choice. Over last 4 decades IVF processes have evolved. There are better tests to predict ovarian response and a number of stimulations regimen to choose from. Better prediction means ovarian hyperstimulation can be predicted and minimised. Cryopreservation of gametes and embryos have become vert successful process, to the extent that policy of freeze all for all has been discussed. It is important that advances in this field are properly evaluated before being put in routine clinical practice for not only pregnancy rates but long term outcomes.
Assessment for contributing causes The investigations done to identify the causes contributing to infertility are to establish ovulation, assess semen analysis and tubal patency. Ovulation: ovulation is assessed by mid-luteal progesterone in regular menstrual cycles. In the presence of irregular menstrual cycles, it is important to do a basal hormonal profile to rule out any underlying hormonal disturbances which have implications for spontaneous as well as treatment-related conceptions. This includes hyperprolactinaemia, PCOS (polycystic ovarian syndrome) and late onset congenital adrenal hyperplasia. The basal hormonal profile should include serum TSH (thyroid stimulating hormone) FSH (follicle stimulating hormone), LH (luteinizing hormone), PRL (prolactin), testosterone and oestradiol
Keywords ICSI; infertility; IVF; pregnancy Semen analysis: semen analysis is an essential step in assessing a couple’s fertility. Results should be assessed against WHO reference values. This test only determines whether sperm are present, looking normal and moving. The positive predictive value of a semen analysis test for predicting pregnancy/nonpregnancy is poor unless there is severe oligozooasthenoteratospermia/azoospermia. Functional sperm tests and tests for sperm DNA fragmentation do not have proven value at present, so should only be done in a research setting
Introduction Infertility affects one in seven couples. Management approaches range from expectant management to ovulation induction, reproductive surgery and assisted conception. In vitro fertilisation (IVF) is the most effective infertility treatment, though not all couples need IVF. The first baby as a result of IVF was born in 1978. Since then there has been an exponential increase in the use of the technology with over 8 million babies born worldwide. The initial application of IVF was in women with blocked fallopian tubes, but over the years, indications have been modified and expanded. The technology has evolved with a number of significant advances in clinical and laboratory techniques and associated regulation.
Tubal patency: tubal patency was traditionally tested by X-Ray based hysterosalpingogram (HSG); however, better methods are now available avoiding radiation such as HyCoSy (hydrocontrast sono-salpingography). HyCoSy has the advantage of being done by the same team as at the fertility clinic, hence a follow up plan can be made at the same time, avoiding radiation and identifying any polyps/fibroids. If HyCoSy is inconclusive, or there are further findings that need treatment prior to IVF/other fertility treatments, a laparoscopy with or without hysteroscopy should be done There is no indication for doing either/both of these procedures routinely for all women undergoing fertility evaluations.
General infertility work up Infertility is defined as a failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse. Increasingly, it is recognized that the desire for a child is not restricted to heterosexual couples and the case mix in clinics reflects this, with increasing proportions of single women and same-sex couples seeking parenthood. The landscape of infertility clinics is changing, hence they should be called fertility clinics rather than infertility clinics. Among heterosexual couples there is a higher proportion of second relationships as well as those in which the partners are older than 35 years of age.
Assessments to optimize preconception health Men and women who attend fertility clinics are generally a young and healthy population who do not attend clinics/hospitals for other reasons. Fertility clinics have a unique opportunity to optimize their general health and provide preconception advice. Body Mass Index: ideal BMI is 18.5e24.9. There is evidence that miscarriage rate is increased both for spontaneous conception as well as treatment related conceptions when BMI is increased Higher BMI is associated with lower pregnancy rates in IVF as well as other fertility treatments.
Abha Maheshwari MBBS, MD, FRCOG Director and Person Responsible, Aberdeen Fertility Centre, Aberdeen Maternity Hospital, Aberdeen, UK. Conflicts of interest: none declared.
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to operate on endometrioma and other ovarian cysts should individualized based on size, access to remaining antral follicles, previous surgery and symptoms. This should be discussed in a multidisciplinary team meeting
Smoking: there is evidence that smoking affects the ovarian reserve (number and quality of eggs). Eggs are only formed once in a lifetime. Hence ovarian age of smokers is increased even if they were ex-smokers. Smoking also affects sperm and is associated with increased DNA fragmentation. There is reduction in IVF success rates when one partner is smoking, and further reduction if both partners are smoking
Ovarian reserve assessment: this can be done by using AFC or AMH or both. The purpose is to determine which stimulation regimen is best based on prediction of response. Both AFC and AMH are very good at predicting poor and hyper responders. This also helps in counselling couples/women
Thyroid: although, there are no recommendations that a thyroid function test should be done routinely, it is recommended by the American Thyroid Association that pre-IVF TSH should be <2.5 mu/l. It is clear that TSH >4 mu/l (i.e. subclinical hypothyroidism) should be treated preconception, but there is controversy for TSH levels between 2.5 and 4 mu/l. Recent evidence from large trials have suggested that presence of thyroid antibodies may affect the outcomes of IVF treatment; however, there is no evidence that giving thyroxine reduces that risk. Hence, it is suggested that there may be another mechanism by which antithyroid antibodies have an impact on the success rates
Endometrial scratching: the value of endometrial scratching is uncertain and it should not be offered routinely Blood borne virus screening: all couples undergoing IVF should have blood borne viral screening done. This is to identify any existing/past infections. According to legislation the gametes and embryos where there may be possibility of transmitting infections should be processed and stored separately. This includes HIV, hepatitis B (both surface antigen and core antibody) and hepatitis C
Rubella: Rubella immunity is determined by serology. However, screening test of rubella is no longer routine in the UK, and everyone is encouraged to have MMR (measles mumps, rubella) vaccination. This is a unique opportunity to immunize those who missed the vaccine
Indications for IVF IVF, though a long and invasive treatment, can be used for any cause of infertility – ovulatory, tubal, male or unexplained (Figure 1). There is an ongoing debate about how wide the indications for IVF should be. Proponents of IVF argue that it is an effective and safe treatment. The risk of ovarian hyperstimulation syndrome (OHSS) can be controlled with the use of preventative measures targeted through ovarian reserve testing. IVF gives the ability to select embryos, and single embryo transfer can be done to prevent multiple pregnancies. In addition, there are cost savings from not pursuing a full aetiological diagnosis which involves investigations and multiple hospital appointments. Opponents of IVF for all causes of infertility argue that it is expensive and invasive. A high proportion of patients will not need it if they are appropriately identified and treated. There are risks associated even with singleton pregnancies as a result of IVF as compared with those of spontaneous conceptions in terms of higher risk of pre-term delivery – small for gestational age babies, congenital anomalies, perinatal mortality, gestational diabetes and pregnancy induced hypertension. There are no head to head trials comparing clinical and cost effectiveness of IVF for all without aetiological diagnosis versus the current practice of step-wise use of IVF. At present, UK practice follows the model of aetiological diagnosis followed by an algorithmic use of IVF (Figure 1).
Assessment to determine prognosis Prognosis of spontaneous and treatment-related fertility is dependent on several factors, most important being age of female partner, ovarian reserve, duration of infertility and parity. Ovarian reserve refers to the number and quality of eggs. In addition to the age of the female partner, the two frequently used assessments are antral follicle count (AFC) which is ultrasound based and serum measurements of anti-Mullerian hormone (AMH). Both are equally effective in predicting hyperstimulation and poor response with the latest studies suggesting that AMH has a slight edge over AFC. The longer the duration of subfertility, the lower the chances of conception. This applies to spontaneous as well as IVF conception. Several prediction models exist across the world based on different datasets to determine a couple’s chances of spontaneous and treatment-related conceptions. They have moderate accuracy and can be used to advise women/couples of their chances. These models in an ideal world should be used to decide who, when and how to treat. However, at present the models are not sufficiently accurate to be used for this purpose. A lot of research is ongoing using data and artificial intelligence to move towards this.
IVF treatment
Pre IVF work up Ultrasound assessment: a pelvic ultrasound should always be done pre-IVF. This is to assess pelvic anatomy and identify abnormalities that need to be addressed prior to IVF. There is evidence that presence of hydrosalpinx halves the success rates, hence it should be removed, or interrupted to prevent hydrosalpinx fluid from accessing the endometrial cavity. The decision
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Once it is decided that IVF treatment is the appropriate way to treat the couple, the couple are counselled about the treatment. IVF involves several steps: stimulating the ovaries with gonadotrophin injections, retrieving oocytes by a surgical procedure, mixing eggs and sperm together to achieve fertilization and then growing embryos in the laboratory until they are ready to be transferred back to the uterus, or frozen for future use.
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Indications for IVF Wait for 2 years
Unexplained infertility
Conventional path based on NICE alogrithm
Investigations to determine etiological diagnosis – Ultrasound – Semen – HSG/HyCoSy – Laparoscopy – Progesterone
Superovulation + IUI
IVF
Wait for 3 years
IVF
Tubal surgery
IVF Wait for 1 year
IVF
Tubal factor
IVF
Male factor
IVF IVF
IUI
IVF
Gonadotrophins Anovulation
Clomiphene citrate
Laparoscopic ovarian diathermy
CC/ Gonadotrophins
IVF
Superovulation + IUI
IVF
Conservative treatment
IVF
Surgery
Endometriosis
Figure 1 Indications for IVF.
desensitization reduces the secretion of LH and FSH. GnRH agonists are commonly used in a ‘long’, starting in the middle of the luteal phase of the preceding menstrual cycle. They may also be started with gonadotropins (‘short’ protocol). GnRH antagonists competitively bind to GnRH receptors in the pituitary gland, blocking the release of LH and FSH. They are usually started on day 5 or 6 of gonadotrophin stimulation or when the leading follicle diameter is 14 mm, and continued throughout gonadotropin stimulation
Ovarian stimulation Multiple eggs are required for the process of IVF. In order to achieve this, ovaries are stimulated with external gonadotrophins. There are various aspects to stimulation regimens. Gondotrophins: there are various preparations available, providing Follicle Stimulating Hormone (FSH) and luteinizing hormone (LH) activity alone or in combination. Broadly speaking, these may be classified as recombinant or urinederived products (Table 1). Multiple trials have been published but no one preparation has been found to be better than the others
Monitoring of the ovarian response to stimulation: ovarian stimulation has to be well controlled as the aim is to develop multiple but not too many follicles. Research indicates that the cumulative success rate of IVF is higher with a higher number of eggs collected. This must be balanced against the risk of OHSS, which increases once the number of eggs crosses 20 Monitoring is done by ultrasound and/or oestradiol monitoring. There is a controversy about the value of oestradiol for monitoring cycles with a normal response. Ultrasound monitoring usually starts on the eighth day of stimulation and is repeated every 2e3 days, until the patient is ready for trigger and
Pituitary suppression: in addition to the gonadotrophins, pituitary suppression is used so that multiple follicular recruitment is possible without inducing an endogenous LH surge. This is done by countering the effect of endogenous gonadotropin releasing hormone (GnRH) through its agonists or antagonists. GnRH agonists interact with the GnRH receptor to produce a ‘flare’ response, followed by desensitization of the pituitary gland (by causing GnRH receptor downregulation) to GnRH. Pituitary
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All egg donors as well as those having fertility preservation should be given antagonist-based regimens as they are shorter and have a lower risk of OHSS.
Variety of ovarian stimulations options available (with permutation combinations from each column options) Gonadotrophins Type
Delivery
Dose increments
Practice points for ovarian stimulation Follicle Stimulating Hormone (FSH) Follitropin Alpha Follicle Stimulating Hormone (FSH) & Luteinizing Hormone (LH)
Recombinant Pre-filled Pen Follitropin Alpha
37.5 iu
Urinary Derived Highly purified human menopausal gonadotrophin (HMG) Biosimilar
75:75iu ratio or 150:150iu ratio
C
C
Multidose or single Vials of Powder and water for reconstitution
C
Pre filled syringe 150 iu/225 iu/ 300 iu prefilled syringes Single vials of 75 iu powder and water for reconstitution
Antagonists based regimens are shorter and have lower risk of OHSS Predicted hyper-responders, egg donors and those undergoing fertility preservation should be commenced on antagonist-based regimens and low dose gonadotrophins. GnRH agonists can only be given for ovulatory trigger if anantagonist is used for pituitary suppression.
Oocyte retrieval (‘egg collection’) Egg collection is the most invasive part of IVF. The majority of procedures are performed transvaginally, under ultrasound guidance. However, women with vaginal agenesis or ovaries that are displaced outside the pelvis may need laparoscopic egg collection. Egg collection is done 34e38 h after the ovulatory trigger to allow the oocyte to mature but to collect it before it is ovulated. The needle is passed through the vagina and follicles are punctured under ultrasound guidance, with fluid collected in test tubes. The fluid is then passed to embryologist who identifies the egg surrounded by cumulus cells (Figure 2), and removes it from the fluid. On average, eggs are retrieved from around 80% of the follicles seen on ultrasound. Although a very safe procedure, there are risks associated with egg collection such as infection and bleeding. There is no indication for giving routine antibiotics, unless the patient has a history of pelvic sepsis, hydrosalpinx or an endometrioma that is traversed by the needle.
Table 1
oocyte retrieval. Hence during a stimulation period of 2 weeks 3 e4 ultrasounds are needed until there are 2e3 follicles of 17e18 mm diameter. Ovulation trigger: once at least 2e3 follicles are present of 17 e18 mm diameter, the final ovulation trigger is given. Traditionally HCG was used for this, acting a surrogate for endogenous LH. However use of HCG is associated with a risk of ovarian hyperstimulation. An alternative approach in cycles using GnRH antagonist for pituitary suppression is to use a single dose of GnRH agonist as a trigger. This works by inducing an endogenous LH surge through its flare effect. The LH surge is sufficient to induce final maturation of the oocyte, but is not sufficient to produce adequate corpus luteum function. As a result, any embryos that are generated should be frozen for future use, or only transferred with added hormonal support In general, based on whether the patient is predicted to be a poor, normal or hyper-responder (as predicted by ovarian reserve test) one can follow the regimen given in Table 2. Apart from predicted hyper-responders, regimens should be chosen based on costs, local availability, patients and clinic preferences.
Laboratory processes Once eggs are removed from the follicular fluid, they are placed in specialized culture media. Not all oocytes that are obtained are mature. Some are at germinal vesicle stage or metaphase I. Sperm preparation: sperm is obtained on the day of egg collection, unless it has been frozen previously. Sperm is prepared to select the most motile sperms. Various techniques have been described to prepare sperm with no one better than other, hence every laboratory needs to use a validated technique with their processes
Preferences of ovarian stimulation regimens Prediction of response
Gonadotrophins
Dose (iu)
Pituitary suppression
Ovulatory trigger
Poor Normal Hyper responders Egg donors Fertility preservation
Any Any Any Any Any
300 150e225 150 150 150e225
Any Any Antagonist Antagonist Antagonist
HCG HCG GnRHagonist GnRHagonist GnRHagonist
Table 2
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uterine cavity), the endometrium is more receptive and embryo selection is better (not all embryos survive in culture to the blastocyst stage). This has led to increase in pregnancy rates per embryo transferred. A higher proportion of embryo transfers are now at blastocyst stage Embryos that develop into blastocyst by day 5 may be transferred or frozen for subsequent treatment. Those embryos that do not form a blastocyst until day 6 are best frozen, as the endometrium becomes asynchronous for implantation by that stage. They may be thawed later and transferred with success rates equal to a fresh embryo transfer. Use of time lapse: many clinics are using undisturbed culture systems, with time-lapse imaging to grow embryos. The undisturbed culture provides an advantage as strict conditions are maintained. Time-lapse imaging also allows the use of algorithms, which scientists can use to select embryos with the highest likelihood of implantation, and deselect those with an abnormal developmental pattern. However, there is no evidence that using such algorithms to pick the best embryos really leads to an increase in live birth rate Culture media used in a laboratory may be single-step or sequential. Single-step media are used throughout the culture period without changing, while sequential media require changing after 3 days. There is an increasing use of single-step media due to the increasing use of time-lapse systems.
Figure 2 A mature egg surrounded by cumulus cells.
Mixing sperm and eggs: sperm and eggs are mixed together by using standard technique of IVF or more invasive ICSI (intracytoplasmic sperm injection) IVF e in IVF prepared sperm are put around the eggecumulus complex and they are incubated overnight. In this process sperm are selected naturally. In addition, as eggs are within cumulus complex, it gives an opportunity for further maturation, in case some were at metaphase I stage. Insemination is done at 40 h post ovulatory trigger
Embryo transfer Embryo transfer is a simple process usually requiring no anaesthesia or analgesia. This is done under transabdominal ultrasound guidance. The outer embryo catheter is placed just beyond the internal os followed by the inner catheter loaded with an embryo. The tip of the inner catheter is placed 1e2 cm below fundus and the embryo is then expelled. Soft catheters are used for embryo transfers with an echogenic tip that is visible on ultrasound. There is no evidence that there is any requirement of antibiotics/bed rest after embryo transfer.
ICSI e ICSI was first used for male factor infertility, i.e. when sperm count is very poor/very few motile sperm are seen. It is also used in cases where there has been previous vasectomy or where there has been previous failure of fertilization using standard IVF. ICSI is done at 38e40 h post ovulatory trigger. In order to do ICSI, cumulus cells are removed from the eggs followed by injection of a single motile sperm into each mature egg. Only eggs that are at metaphase II stage can be injected. It is an invasive technique and has a 5% risk of damage to eggs; in addition, the selection of sperm is done by embryologists as opposed to natural selection as in IVF Although there is no evidence that ICSI leads to higher pregnancy rates for non-male factor infertility, the proportion of cases having ICSI is rising globally. Many scientists are using them for unexplained infertility or when there are small numbers of eggs. There have been attempts to use hyaluronate binding and high resolution microscopes to select sperm but none of them has proven in large randomized trials to be better than current morphological-based selection.
Frozen embryo transfer The ‘best’ embryo is chosen for the fresh embryo transfer. Any remaining embryos that appear to be of sufficiently good quality may be frozen. Frozen embryo can be used if fresh embryo transfer is not successful or for a sibling pregnancy if fresh embryo transfer was successful. Freezing used to be done by slow freezing but now most clinics prefer vitrification. Embryo survival rates with warming following vitrification are over 95%. Luteal support Luteal support is essential in IVF treatment where cycles have had external gonadotrophins. It is usually started on the day of egg collection and continued at least up until the day of a pregnancy test. Most clinics continue it until 7e8 completed weeks where as some continue it until 12 weeks. There is no evidence in the literature that continuation beyond the pregnancy test leads to an improved pregnancy rate. Progesterone given vaginally is the most commonly used luteal support. Those who cannot tolerate tablets can be given vaginal gel. Alternative routes for progesterone are subcutaneous, intramuscular and oral. There is no evidence that one is
Embryo Culture: approximately 60e80% of injected/inseminated eggs turn into embryos. These embryos are then cultured in specified conditions. In the early days of IVF, embryos were put back into the uterus 2 or 3 days after culture. With advances in culture conditions we are now able to grow embryos for much longer. This means that embryos can be cultured to day 5 or 6, i.e. blastocyst stage. It is considered that embryo transfer at blastocyst stage is better because it is more physiological (as this is the stage in natural conception when the embryo reaches the
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predicted by the above described risk factors. This is self-limiting once the effect of exogeneous HCG has disappeared. If it is diagnosed prior to embryo transfer, embryos should not be transferred and should be frozen for future use
better than others. There is no evidence that adding oestrogens to progesterone leads to an improvement in pregnancy rates. HCG is rarely used for luteal support, due to the risk of OHSS.
Complications e OHSS Late OHSS: this occurs 9 or more days after the trigger. This is usually due to endogenous HCG and occurs in those who are pregnant. Known risk factors are only poorly predictive of the risk of late OHSS, which is more likely to be severe and prolonged than the early form
Ovarian hyperstimulation (OHSS) is an iatrogenic complication of ovarian stimulation with exogenous gonadotropins. The pathophysiology involves ovarian enlargement and fluid shift from the vasculature into the third space. The clinical severity of OHSS can be classified as shown in Table 3.
Symptoms and management of OHSS Symptoms of OHSS are non-specific such as nausea, vomiting and abdominal discomfort. Hence, a high index of suspicion should be maintained for anyone having ovarian stimulation. Patient and doctor awareness are key. Alternative diagnoses should be considered in the presence of severe abdominal pain or fever, including: pelvic infection, complication of an ovarian cyst, intra-abdominal haemorrhage, ectopic pregnancy, appendicitis and gastroenteritis. Initial management should include clinical assessment and investigations to classify it as mild, moderate or severe (Table 3). Management is usually supportive. Specialists in reproductive medicine should be involved in care, as they are most likely to have the appropriate expertise and experience. Women with severe OHSS or those who have moderate OHSS but are finding it difficult to manage pain relief or fluid intake should be considered for hospital admission. The main aspects of care are fluid management, thromboprophylaxis and drainage of effusions. Intensive care colleagues should be involved if features of ‘critical’ OHSS are present.
Risk factors for OHSS The risk is higher in women who have: An antral follicle count (AFC) 20 Higher levels of anti-Mullerian hormone (AMH) Polycystic ovaries Younger women Lower BMI Higher number of medium-sized follicles during stimulation Higher oestradiol levels during the stimulation phase Use of hCG for luteal support (rather than progesterone) Previous OHSS Higher number of oocytes collected Achievement of pregnancy Types of OHSS Early OHSS: this occurs within 7e9 days after the triggering ovulation and is caused by exogenous HCG. This can be
Prevention of OHSS Various strategies have been used to prevent OHSS: Identification of appropriate cases based on tests of ovarian reserve Low dose stimulation for those predicted to be hyper responders GnRH agonists for ovulatory trigger instead of HCG; no HCG for dual trigger Planned freezing of all embryos. This would avoid late OHSS by avoiding pregnancy in the stimulated cycle.
Classification of OHSS Mild OHSS
Moderate OHSS
Severe OHSS
Critical OHSS
Abdominal bloating Mild abdominal pain Ovarian size usually <8 cma Moderate abdominal pain Nausea vomiting Ultrasound evidence of ascites Ovarian size usually 8e12 cma Clinical ascites (occasionally hydrothorax) Oliguria (<300 ml/day or <30 ml/h) Haemoconcentration Haematocrit >45% Hyponatraemia (sodium <135 mmol/l) Hypo-osmolality (osmolality <282 mOsm/kg) Hyperkalaemia (potassium >5 mmol/l) Hypoproteinaemia (serum albumin <35 g/l) Ovarian size usually >12 cma Tense ascites or large hydrothorax Haematocrit >55% WCC >25 000/ml Oligo/anuria Thromboembolism Acute respiratory distress syndrome (ARDS)
Policy of freeze all For those who are at risk of ovarian hyperstimulation, freezing of all embryos is associated with a reduced risk of OHSS, especially late OHSS which is difficult to predict. Clinical trials show that pregnancy rates of thawed frozen embryo transfers are similar to those of fresh embryo transfer. Hence it has been suggested that we should freeze all embryos and thaw and transfer them at a later date in the interests of safety, without reducing efficacy. Randomized trials have suggested that the pregnancy rates are 15% higher for a freeze-all policy for those predicted to be hyperresponders. However, no difference has been shown for normal responders. In addition, it has been shown that the risk of small for gestational age babies and preterm deliveries is reduced in
a
Ovarian size may not correlate with severity of OHSS in cases of assisted reproduction because of the effect of follicular aspiration.
Table 3
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thawed frozen embryo transfers when compared to fresh. However, thawed frozen embryo transfers are associated with higher risk of large for gestational age babies and increased risk of preeclampsia. Hence, there is an ongoing controversy about the value of freeze-all, other than for predicted high responders where it does appear to offer a significant benefit by abolishing the risk of late OHSS.
RCOG Guidance on OHSS- Green top guidance https://www.rcog. org.uk/en/guidelines-research-services/guidelines/gtg5/. Roque M, Haahr T, Geber S, Esteves SC, Humaidan P. Fresh versus elective frozen embryo transfer in IVF/ICSI cycles: a systematic review and meta-analysis of reproductive outcomes. Hum Reprod Update 2019 Jan 1; 25: 2e14. Maheshwari A, Bhide P, Pundir J, Bhattacharya S. Routine serum thyroid-stimulating hormone testing-optimizing pre-conception health or generating toxic knowledge?. Hum Reprod 2017 Sep 1; 32: 1779e85.
Pre-implantation genetic testing Pre-implantation genetic testing for aneuploidy (PGT-A) refers to testing embryos for genetic abnormality and replacing only an embryo that is chromosomally normal. When there is a known genetic abnormality in either/both parents it is called preimplantation genetic diagnosis (PGD). Trails show that the transfer of screened euploid embryos is associated with high success rates. However, the value of PGT-A has not been proven through randomized trials, and it should be kept in mind that this is a method of embryo selection rather than embryo improvement. Embryo biopsy is carried out on the trophectoderm at the blastocyst stage and carries a risk of embryo damage. Embryos need to be vitrified until the results of genetic testing are available. Further, the occurrence of mosaicism in blastocyst embryos poses a challenge to accurate diagnosis. As a result, PGT-A is not standard treatment at present. A
Practice points C
C
C
C
FURTHER READING HFEA webpage on add ons https://www.hfea.gov.uk/treatments/ explore-all-treatments/treatment-add-ons/. NICE fertility Guidance- CG156 https://www.nice.org.uk/guidance/ cg156.
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Indication of IVF are increasing, and it is now most frequently performed fertility treatment AMH and AFC are good predictors for poor and hyper response following ovarian stimulation There are no indications for
C
7
Doing endometrial scratching Using ICSI for non-male factor infertility Selecting sperm using high hyaluronidase binding Freezing all embryos for all Pre implantation Genetic testing for aneuploidy
A high index of suspicion should be maintained for OHSS for anyone undergoing ovarian stimulation. Preventive strategies should be adopted wherever possible. Involve IVF specialists Continuing luteal support beyond positive pregnancy test is not based on evidence
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