Monday, 27 April 2020

Vol. 9 April 2020: UNEXPLAINED SUBFERTILITY: Definition, Investigations & Management

Unexplained Subfertility: Definition, Investigations & Management
     Author: J. Adeghe PhD, FRCOG.


In about 15% of couples experiencing difficulty in conceiving, investigations do not reveal any abnormality, therefore this diagnosis is labelled as unexplained. Many couples find this label frustrating and often questions it and say, “if there is no underlying cause, why am I not getting pregnant?”.

What the term ‘unexplained infertility’ really means is that basic assessment of the three pillars of fertility – ovaries/ovulation, fallopian tubes and sperm – have not shown any obvious abnormality. It does not mean that there are no problems with other bodily systems that must function well for pregnancy to occur. For example, the endocrine organs (e.g. thyroid gland), immune system, nutritional status, must function optimally for pregnancy to occur and develop normally. In fact, these other organs are generally not tested as part of first line investigation into subfertility. In essence the so-called unexplained subfertility is really ‘subfertility of no obvious cause’, because the couple have not been investigated well enough. The obvious causes being tubal, sperm factor or ovulatory dysfunction.

Treatment options that are often offered to couples with Subfertility of no obvious cause usually  include:


a 1)  ‘Wait and See’ approach (expectant management), especially if the couple have been trying for less than 2 years and the woman is less than 30 years old. The couple is advised to keep ‘practising’ and hope for a pregnancy.


S2) Simple ovarian stimulation with Clomifene or Letrozole tablets, with ultrasound follicle tracking.


c 3)  Intrauterine insemination (IUI) with mild ovarian stimulation.


I 4) IVF treatment, especially if the woman is over 35 years age, or have been trying for 3 years or more.


The management dilemma arises, when one or more or the above treatment modalities are unsuccessful. What to do? How to proceed?


Further tests should be carried out to diagnose the underlying cause of subfertility of no obvious cause. Investigations should be structured and directed by the couple’s medical history and other relevant findings.

The following investigations should be considered.

Laparoscopy
In many cases tubal patency test as part of first line fertility investigations is assessed by hysterosalpingography (HSG) or Hysterosalpingo-Contrast-Sonography (HyCoSy). While both methods are effective in checking whether or not fallopian tubes are patent, they give no indication of any background pelvic conditions often referred to as peritoneal factors - peritubal or tubo-ovarian adhesions, or endometriosis, conditions that can impair fertility. In addition to being diagnostic, laparoscopy provides an opportunity to carry out therapeutic procedures e.g. division of adhesions to restore normal pelvic anatomy, or diathermy to endometriotic deposits.

·        Hysteroscopy
Hysteroscopy is a minor endoscopic procedure to visualise the uterine cavity in order to identify and treat any endometrial lesions present. This is a simply procedure that can be done on an outpatient basis. It is often overlooked in discussions and publications on investigations of subfertility of uncertain cause. Clearly, it should be in the forefront of investigations because endometrial lesions can impact on implantation. Conditions such as polyps, adhesions, inflammatory changes, can impair implantation. In my clinic, endometrial factors (polyps, adhesions, septum, inflammatory changes) are found in about 14% of women with recurrent implantation failure.
Hysteroscopy should be performed in women with recurrent unsuccessful assisted conception treatment cycles.

 Infection screen 
Various infections can impair fertility at every level of the reproductive pathway including fertilisation, implantation, and embryo viability. Infections are causal to many cases of miscarriage. It is therefore important to conduct a thorough screening for infections in cases of subfertility of no obvious cause. A recent research publication suggests that sperm cells carrying human papilloma virus have increased DNA fragmentation which can impair the ability of sperm to fertilize. Infection screen can be carried out on first urine catch using polymerase chain reaction (PCR) technique. This identifies exposure to chlamydia trachomatis, gonorrhoea, herpes virus I & II, gardnerella, trichomonas, and ureaplasma urealyticum, mycoplasma hominis. Other pathogens include cytomegalovirus and toxoplasmosis. If this methodology is not available a simple high vaginal swab for microscopy, culture and sensitivity is also good and effective. Tuberculosis is becoming resurgent in many communities, therefore a thorough medical history to identify possible exposure should be taken. Previous tuberculous infection may have caused damage to the
fallopian tubes or caused granulomatous endometritis, and remain asymptomatic.
It goes without saying that infection screening should be carried out in both women and men. In my practice, testing of the man is carried out on a first urine catch in the morning.

Detailed Semen Analysis
Semen analysis should be re-visited. Particular attention should be paid to leucocyte count in the semen which may be an indication of infection in the testis/epididymis (epididymo-orchitis), prostate (prostatitis) or seminal vesicles.
Specialist tests such as anti-sperm antibodies (IgG and IgM subtypes) should be carried out. The role of anti-sperm antibodies in subfertility is controversial but there is reasonable evidence that they can impair sperm transport through cervical mucus and antibodies directed against the sperm head can impair fertilisation. In cases where over 50% of sperm are coated with anti-sperm antibodies, assisted reproductive treatment using ICSI technique is indicated.
Sperm DNA fragmentation have been shown to impair sperm function but at present there is no consensus on what level of fragmentation is clinically significant. Testing may be carried out but management decisions should be made taking other sperm parameters and clinical picture into consideration.

 Immunological tests

Male
Testing for immunological factors in men involves testing for antisperm antibodies coated onto sperm. This was mentioned briefly above. Historically antisperm antibodies were tested for using blood samples but numerous studies have shown that circulating antisperm antibodies correlate poorly with infertility. The only clinically relevant tests are those based on sperm surface antibodies which can impede sperm motility and fertilizing ability.

Female
In women, testing for Natural Killer cells (NK cells) in the blood or within the endometrium may be clinically relevant to fertility. This is a controversial area and should be dealt with by clinicians who have the appropriate training and experience.

Management Plan
The findings from further investigations would determine the treatment plan. However, general measures to optimise successful outcome to treatment is of utmost importance. 

1]  Lifestyle review and advice

This is the first line approach to management. Although lifestyle review with correctional changes should be done as the pre-conception advice, it is often overlooked. At this stage when time has moved on and there is repeated treatment failure it is time to ‘crack the whip’ or ‘read the riot act’. Lifestyle review and corrective measures should focus on:

·        Cessation of smoking – both partners

·        Stops excessive alcohol consumption

·        Reduce Caffeine intake (no more than two cups of coffee a day)

·        Weight reduction through diet control and exercises. Aim for BMI of <30

·        Dietary changes to adopt the components of the Mediterranean diet – avoid red meat, eat oily fish, reduce carbohydrate intake

·        Eat green vegetables and fruits

·        Reduce stress – observe periods of ‘down time’ where you do nothing but just ‘gaze’, listen to soothing music, yoga, etc.

·        Take Folic acid tablet 5mg once a day

       2] Eliminating or correcting any abnormal findings uncovered by investigations, including:

·        Salpingectomy if there is hydrosalpinx

·        Resection of submucous fibroids

·        Endometrial polypectomy if polyps are found in the endometrial cavity

·        Correcting low levels of Vitamin D

·        Treating underactive thyroid

·        Antibiotic treatment for men with increased leucocytes in semen

·        Treatment of underlying infection in both partners

        3]   Solutions: Note that I have said ‘solutions’ rather that treatment. This is because in helping
              couples create families, we should other options that other than assisted conception
              treatments.

              IVF/ICSI 
              Careful consideration should be given to treatment planning. Review of previous treatment
               cycles to see what worked or didn’t. Procedures and strategies to optimise success include:

              -Endometrial scratch

              -Blastocyst culture

              -Augmented luteal support with combination of oestrogen tablets and injectable

               progesterone

              -Elective freeze of embryos and subsequent frozen embryo transfer

              IVF/ICSI using donor gametes

              For women with low AMH levels where egg numbers and quality are compromised, use of

              donor egg is indicated. Similarly, if sperm quality is very poor, donor sperm may be the way

              forward. Use of donated embryos is also an option

             Surrogacy
              Surrogacy should be considered if investigations indicate a uterine/endometrial problem
              that did not respond to treatment. In this situation, host surrogacy is an option.

              Adoption
              When treatment has failed repeatedly and the prospect of success with further treatment is
              bleak, adoption should be considered. This may not be acceptable for some couples but is
              one way to create a family. There are many children awaiting adoption in many countries
              though it has to be said that adoption laws in the UK are tough.



Saturday, 18 April 2020

Vol. 8 April 2020 - CLINICAL GOVERNANCE PROPERLY IMPLEMENTED CAN GALVANISE THE DRIVE TO HEALTHCARE EXCELLENCE IN NIGERIA


Clinical Governance properly implemented can galvanise the drive to Healthcare excellence in Nigeria

The diagnosis of dysfunction in the Nigerian Healthcare system is self-evident. The magnitude of the problem and the multitude of underlying factors have been discussed ad nauseam by several commentators. Government actions to improve healthcare delivery have proved ineffective and amount to mere rhetoric for political gains. Collective action by all stakeholders is required. More so by doctors and all healthcare professionals. Change for the better will only happen if there is true commitment to working towards well defined quality standards.

In the course of my research into health quality improvement in Nigeria, I came across a paper which resonated well with my own thoughts. The paper is titled “Guidelines for Performance Management in Hospitals” by Mobola Olatawura and Chukwuka Monye, both of Ciuci Consulting.  The link to the paper is below:


The paper makes a compelling case for Clinical governance as an essential tool for quality healthcare improvement in Nigeria. It gives a step-by-step guide on the implementation of effective clinical governance structure in Nigeria and other developing countries. By the way, clinical governance is well entrenched in U.K. National Health Service (NHS).

Clinical Governance is a framework of activities for maintaining and improving the quality of care within a healthcare system. The components of clinical governance include:

a)     Risk Management

b)    Clinical audit

c)     Education, Training and Continuous Professional Development

d)    Evidence-based care and effectiveness

e)     Clients’ experience and involvement

f)      Staffing and staff development

These components should work together in an integrated manner to provide the basis for a sustained quality service delivery. The paper cited above is not the first or the only one to emphasise the importance of clinical governance. Many others have presented well written papers on clinical governance but it has never been adopted on a national basis and has never been taken seriously enough.

The paper commented that in the banking and finance industry, corporate governance is stressed and violation of it can attract jail sentences. They go on to ask “Is it not disturbing that banking and finance sector is given more attention than the health sector?” They make the point that health institutions in Nigeria lack effective clinical governance structures and that accountability, transparency and a focus on quality assurance are somewhat lacking. According to the authors, an investigation carried out in a Nigerian government owned hospital, showed that the number of deaths and errors that occur in the hospital are unknown and there are no policies to encourage transparency, perform regular audits, detect, log and prevent repeat of errors.    

We must stop the rot. Covid-19 crisis is ongoing and should serve as an eye opener!.
There should be a national strategy for healthcare quality improvement. Clinical governance has to be at core of that strategy. If clinical governance structures are properly implemented, the benefits will flow to every hospital, every health clinic and every citizen needing medical care in Nigeria.

Friday, 17 April 2020

Vol 7, APRIL 2020 - PRE-CONCEPTION ADVICE & MANAGEMENT (NICE GUIDELINES)


PRE-CONCEPTION ADVICE AND MANAGEMENT (NICE GUIDELINES)



Advice for all women (16 years to 45 years Female)



1.           Of 100 couples (in which the woman is aged under 40years) having regular sexual intercourse without contraception:



o   About half of those who do not conceive in the first year will do so in the second year.



o   The remainder will take longer and some of these may need help for them to conceive.



2.           Sexual intercourse every 2 to 3 days optimises the chances of pregnancy. 



There is no need to plan intercourse to coincide with ovulation – this does not increase the chances of success and can cause stress for the couple.



3.           Women over 35 years have an increased risk of miscarriage, chromosomal abnormalities and obstetric complications compared to younger women.



4.           Advice on folic acid:



o   Normal risk of neural tube defect (NTD) should take the standard dose of 400 mcg

daily and once pregnant, to continue this until 12 weeks of pregnancy.



o   Women at high risk of NTD, or taking antiepileptic medication, should take 5 mg daily until the 12th week of pregnancy. 



o   Women with sickle cell disease, thalassaemia or thalassaemia trait, should take 5 mg daily throughout pregnancy.



o   Women with high BMI (30 kg/m²) should take folic acid 5 mg daily starting at least 1 month before conception and continue until 12 weeks.



5.           Advice on Diet:



o   Recommend a healthy, balanced diet.  Diet and nutrition before conception or during pregnancy are important as it can impact on pregnancy outcomes and the health  of the mother and her baby.





6.           Advice on weight management:



o   Women with a healthy weight (BMI 18.5 – 24.9 kg/m²) before becoming pregnant reduces the risk of pregnancy complications.

o   Women of high BMI (30 kg/m² or more ) have potential health risks including:



§  Reduced fertility

§  Reduced success rate from fertility treatment

§  Increased risk of miscarriage

§  Gestational diabetes

§  Gestational hypertension/pre-eclampsia

§  Big babies and should dystocia

§  Preterm delivery



7.           Women of low BMI (less than 18.5 kg/m²) have potential health risks of being underweight,

Including:



§  Reduced fertility

§  Miscarriage

§  Premature delivery

§  Low birth weight

§  Gastroschisis

                           

8.           Advice on smoking:



o   Smoking is associated with reduced fertility and reduced success rate from fertility treatment



o   Smoking is associated with growth restriction of the baby



o   Suggest referral to smoking cessation service.



9.           Advice on alcohol consumption



o   Avoid alcohol if trying to conceive and during pregnancy.



10.         Advice on illicit drug use:



o   Women planning pregnancy who use illicit drugs should stop, including so-called “legal highs”.  Those who are unable to stop should be referred to a specialist service.



11.         Advice on immunisation



o   Determine if a woman planning a pregnancy is protected against rubella.  For example documentation of having received two doses of rubella containing vaccine, or on a positive antibody test for rubella.



o   Refer to GP if not immune to rubella, for MMR vaccine.  Vaccine should not be given to immunocompromised or pregnant woman.  Women who are not pregnant should avoid pregnancy until one month after administration of vaccine.



12.         Advice on Cervical Screening



o   All women planning pregnancy who are due a cervical smear to have the test as soon as possible, before becoming pregnant.



13.         Multiple Pregnancies



o   Multiple pregnancies are associated with an increased risk of adverse outcomes in pregnancy such as miscarriages, bleeding, pre-term delivery, high blood pressure and diabetes.



o   Due to the increased risk mentioned above, we strongly advise the replacement of single embryo in IVF especially in women aged below 37 years.




Vol 6, APRIL 2020 - MANAGING WEIGHT TO OPTIMISE FERTILITY


MANAGING WEIGHT TO OPTIMISE FERTILITY
Sarah Baker RM, Fertility Midwife, St Jude's Hospital, Wolverhampton.

Maintaining a healthy weight is not only important for general wellbeing; studies have shown that obesity is also linked with a decline in overall fertility, the success rates of potential fertility treatments and pregnancy outcomes.


Increasing insulin levels associated with raised BMI can cause hormonal imbalances which have a direct impact on fertility.
            - In women, this can cause an increase in the levels of androgens (male hormones) which can inhibit ovulation causing irregular menstrual cycles. Even a small reduction in weight of just 5-10% can help to restore normal ovulatory functions and improve pregnancy rates.
- In men, severe obesity has been linked to raised oestrogen levels and decreased testosterone levels, which can affect sperm production, reducing sperm count and motility. Metabolic syndrome, a condition caused by obesity, can also lead to symptoms of erectile dysfunction.

Body Mass Index (BMI) may be used as a measure to determine healthy weight parameters, and is calculated by dividing weight (in kilograms) by height squared (in centimeters).

A normal BMI is defined as between
18.5 and 24.9.
A BMI of below 18.5 is in the underweight range.
A BMI between 25 and 29.9 is classified as overweight
BMI of >30 is categorised as obese.

          The following factors associated with raised BMI may complicate Fertility Treatments:
- Poor response to ovarian stimulation medications
- Difficulty titrating the dose of medications, in particular for women with
Polycystic Ovaries Syndrome (PCOS) and a greater risk of Ovarian Hyper-stimulation Syndrome (OHSS)
- A reduction in the number of eggs collected and more difficult Egg Collection/ Embryo Transfer procedures
- Lower success rates

In addition, raised BMI in pregnancy is associated with an increased risk of miscarriage, hypertension, Gestational Diabetes, pre-eclampsia, still birth and a number of other obstetric complications.

Information on how changes to diet and exercise regimes may aid weight loss can be found on the Department of Health website: The Eatwell Guide and Start Active, Stay Active Initiative.
https://www.gov.uk/government/publications/the-eatwell-guide
https://www.gov.uk/government/publications/start-active-stay-active-infographics-on-physical-activity 

St Jude’s Hospital does not discriminate against women or their partners based on BMI and never refuse Fertility Treatments on this basis. However the clinic is committed to doing all we can to promote good health amongst our patients and assisting in weight loss journeys wherever possible, with a view to improving treatment success rates, lowering complication rates and improving pregnancy outcomes.
Spandorfer, Jump, Goldschlag et al: Obesity and in vitro fertilization: negative influences on outcome J Reprod Med 49: 973-977 2004


Maheshwari, Stofberg and Bhattacharya: Effect of overweight and obesity on assisted reproductive technology – a systematic review Human Reproduction Update 13: 433-444 2007

Robinson, O’Connell, Joseph et al: Maternal Outcomes in Pregnancies Complicated by ObesityObstetrics and Gynecology 106: 1357-1364, 2005


Chu, Callaghan, Kim et al: Maternal Obesity and Risk of Gestational Diabetes Mellitus Diabetes Care 30: 2070-2076 2007


Dokras, Baredziak, Blaine et al: Obstetric Outcomes after In Vitro Fertilization in Obese and Morbidly Obese Women Obstetrics and Gynecology 108: 61-69 2006

Diamanti-Kandarakis E, Bergiele A. The influence of obesity on hyperandrogenism and infertility in the female. Obes Rev. 2001; 2: 231-8

Ramsay JE, Greer I, Sattar N. Obesity and reproduction. British Medical Journal. 2006; 333(7579): 1159-62.

https://www.gov.uk/government/publications/the-eatwell-guide

https://www.gov.uk/government/publications/start-active-stay-active-infographics-on-physical-activity

https://www.nhs.uk/common-health-questions/lifestyle/what-is-the-body-mass-index-bmi/

Tuesday, 14 April 2020

Vol 5, APRIL 2020 - LOW AMH AND IVF-ICSI TREATMENT OUTCOMES: ANALYSIS OF 15YRS DATA



LOW AMH LEVELS AND FERTILITY TREATMENT OUTCOMES: ANALYSIS OF 15 YRS DATA


Authors:  Sarah Baker RM, Fertility Midwife, St Jude’s Women’s Hospital, Wolverhampton, UK.
R. Sriskandakumar, MSc, Senior Embryologist, St Jude's Women's Hospital, Wolverhampton, UK
J. Adeghe PhD, FRCOG, Consultant - Gynaecology/Reproductive Medicine.


Introduction

This audit looks at the relationship between patient AMH levels and associated fertility treatment outcomes. The audit includes 157 women, who had 296 treatment cycles over a 15 year period from 2003 to 2018. The vast majority of these cycles were carried out between 2010 and 2018 (98% of cycles), however data of all cycles for women included in the audit were completed hence the inclusion of cycles from earlier years.

St Jude’s Hospital has been routinely testing AMH levels in female patients undergoing fertility treatment for over ten years. The Doctors Laboratory processes these samples and formulates results. Bloods are tested for Anti-M├╝llerian Hormone (AMH), which is produced by developing follicles in the ovaries. AMH levels are low during childhood, increase during puberty and reach a peak in early adulthood. Levels then gradually decline in line with ovarian function as the number of follicles present in the ovaries decrease until levels are undetectable following menopause. AMH measurement is therefore used as an indication of ovarian reserve and is now used routinely to guide fertility practitioners. Aside from fertility, AMH has other diagnostic value in investigating abnormal sexual development in babies and children and monitoring response to treatment of ovarian tumors. (The Doctors Laboratory, 2017)

AMH is a relatively new diagnostic test, and was frequently practiced at St Jude’s Hospital before it became widely recognised as a diagnostic fertility test. Therefore the hospital has accumulated a vast data set which may be utilised to identify trends, inform practice and advise patients.

The demographic of women seen by St Jude’s Hospital differs from that seen at many other clinics, in particular NHS clinics. The majority of women seek treatment at the clinic because they are ineligible for NHS treatment. This may be due to factors such as increased maternal age <40 years, raised BMI <30, or low ovarian reserve/premature ovarian failure. It is important to factor this into conclusions made from the audit, in particular when making wider comparisons of success rates etc. Due to the volume of women seen by the clinic with a low AMH (<5pmol/L), there was a particular interest in this group to better advise them of their relative success rates for IVF treatment. 


Rationale

The purpose of the audit was to collect and utilise the vast data set accumulated by St Jude’s Hospital from testing patient AMH levels over a 15 year period, and analyse data to better inform patients of projected treatments outcomes and success rates based on data from women with a similar demographic to themselves. This will allow the clinic to give honest real estimates and better advise women to aid in their decision making process when undergoing fertility treatment. 


Prediction

 Expectations of results were based on clinical experience and theory as follows:

·        As AMH declines with age, the expectation is that number of eggs collected would also decline.

·        There would be an increase in the incidence of abandoned cycles, or cycles that do not proceed to ET

·        There would be an increase in the number of embryos transferred for cycles which did proceed to Embryo Transfer which decreasing AMH/increasing maternal age, in view of HFEA guidelines. (Guidelines state that a up to three embryos may be transferred for women over the age of 40, although this should be carefully considered and discussed with healthcare professionals in view of the risk of a multiple pregnancy)

·        The prediction is that pregnancy rates will increase with an increase in AMH up to a peak (estimated to be approximately 40pmol/L), beyond which point rates are likely to decrease in view of co-morbidities associated with a raised AMH such as PCOS.

·        It is expected that starting dose and total dose of Stimulation medication will decrease as AMH increases, as women with lower AMH levels need higher doses of medication to stimulate a good ovarian response, compared to those with higher AMH levels.

·        It is predicted that duration of stimulation may be longer for women with lower AMH levels or increased maternal age, as ovarian response may be less favourable and take longer compared to younger women with a higher AMH level.

·        Ongoing pregnancy rates and live birth rates may be lower as women’s age increases in view of the increased risk of miscarriage associated with advancing maternal age. 


Data Collection

TDL laboratory were contacted by the hospital’s Senior Clinical Embryologist, Rasiah Sriskandakumar to request data relating to patients of the clinic. A list of 163 lab results was obtained inclusive of a lab reference number, patient’s initials, date of birth and AMH levels.

This data was used to search the clinical accounting system, Midex. By searching for women’s date of birth and matching results by initials, registration numbers and full names were obtained, which enabled us to pull out current and archived records to audit and collect data.

However for six of the lab results, no match was found on searching the date of birth on Midex and women’s names or registration numbers could not be identified; therefore these AMH results could not be included in the audit. This may be explained by the fact that the Midex accounting system was not routinely used for some of the earlier cycles included in the audit. Some patients may have also had blood tests for AMH level done, and then not proceeded to have any treatment, again in which case in previous years all data may not have been entered onto the Midex system.

Hospital staff facilitated locating patient records from the filing system and archive room. Unfortunately a further 25 records could not be located in either the current patient note filing system or from archived files, and these results had to again be excluded from the audit as no data could be collected.

Data was then collected from patient notes to include name and registration number, date of birth, age at point of treatment, AMH, treatment type, clinical protocol used, start date and dose of stimulation and total dose, duration of stimulation, medication used, number of eggs collected, number of embryos transferred and clinical outcomes. 


Data Analysis

Data was separated into different sets and analysed. An initial overview of pregnancy rates was conducted, then data was grouped based on treatment typed, splitting into ICSI/IVF, IUI/IUDU/follicle tracking and FET cycles. Within each group data was ordered based first on AMH and then by age, and analysed for each to identify trends (see excel document). Demographics for each group were analysed, and a summary of mean dosage of medication, mean number of eggs collected and embryos transferred tabulated, and results collated to see how many cycles were abandoned/did not proceed to ET/had no outcome information recorded, and how many resulted in positive and negative pregnancy tests. Comparison of the percentages of the above parameters enabled the establishment of correlations and an estimate of the likelihood of different outcomes for each group.

Results of an AMH of less than 5 were then further disseminated into groups with an interval of 1pmol/L, as there was a particular interest in women with a lower AMH and their treatment outcomes.  Analysis was based on the same summary table templates and parameters outlined above. 


Results

Data was broken down into different sets and analysed in order to identify correlations and make conclusions. Data was initially separated by the nature of treatment, into IVF/ICSI, FET, IUI/IUDI and simple follicle tracking. Summary tables were assimilated for each set and then formulated into tables and also represented in graphical form. Data was then analysis in order of ascending AMH and in age order to identify trends.

IVF/ICSI Treatment

IVF and ICSI treatment cycles included in the audit were ordered on both AMH and Age to identify any potential correlations.

AMH

All IVF/ICSI cycles included in the audit were ordered according to ascending AMH level, the grouped in intervals of 5poml/L. Data was summarised for each group on average AMH, average age, average start dose and total dose of stimulation, average duration of stimulation, average number of eggs collected and number of embryos transferred, percentage of cycles  which were abandoned/did not proceed to Embryo Transfer or had no information recorded, and percentage of positive and negative pregnancy test results. The data was formulated into a table, then into a graphical format to identify emerging trends and relationships.

AMH
0-5
5-10
10-15
15-20
20-30
30-50
50+
Data in set
54
56
25
34
23
16
15
Avg age
38.4
38
35.7
34.2
33.4
35.1
31.7
Avg AMH
2.3
7.45
12.6
17.3
26.2
42
63.2
Avg start dose
403
315
294
249
232
225
185
Avg total dose
3359
2905
2433
2321
2123
2114
1745
Avg duration of stim
11.3
11.1
11.24
11.4
10.8
12
11.6
Ave no eggs
3.3
7.5
8.12
8.8
11.4
11.3
8.8
Avg embryos transferred
1.2
1.5
1.4
1.7
1.7
1.81
1.2
Abandoned cycles
5.6
5.4
4
2.9
0
0
6.7
No ET/failed fert
22.2
14.3
12
8.8
4.3
0
20
No information recorded
9.3
5.4
4
0
0
0
0
Positive test
20.4
33.9
40
23.5
43.5
43.75
26.7
Negative test
42.6
41.1
40
64.7
52.2
56.25
73.3
Pos test (of completed cycles)
32.4
45.2
50
26.7
45.5
43.75
36.4
Neg test (of completed cycles)
67.6
54.8
50
73.3
54.5
56.25
63.6



Findings from analysing data from IVF/ICSI cycles arranged and grouped in order of ascending AMH levels are as follows:

-         Mean age decreased with ascending AMH values. So generally older women had a lower AMH and younger women had a higher AMH level.

-         Mean start dose and mean total dose of stimulation medication decreased with increasing AMH values.

-         Mean number of eggs collected increased with increasing AMH levels up to the 20-30pmol/L group, after which point mean number of eggs was static in 30-50pmol/L group, then decreased with an AMH of >50pmol/L.

-         As AMH increased the number of abandoned cycles and cycles which did not proceed to ET decreased up to the point of 30-50pmol/L, again after which the incidence increased again with AMHs of >50pmol/L.

-         The proportion of positive pregnancy tests increased from AMH of 0pmol/L up to 30pmol/L, the 30-50pmol/L group was static at 43.8% and the >50pmol/L group had a lower proportion of positive tests at 26.7%. An anomaly was observed in the 15-20pmol/L group, with lower than expected positive test rate at just 23.5%.

These results would indicate that optimal AMH level for treatment outcomes would be approximately 30pmol/L.  A low AMH level or very high AMH level >50pmol/L are associated with poorer outcomes and lower success rates.

 





AMH 0-5pmol/L

All IVF/ICSI cycles included in the audit for women with an AMH of <5pmol/L were analysed further. Ordered according to ascending AMH level, these cycles were split down into smaller groups in intervals of 1pmol/L. Data was summarised for each group on average AMH, average age, average start dose and total dose of stimulation, average duration of stimulation, average number of eggs collected and number of embryos transferred, percentage of cycles  which were abandoned/did not proceed to Embryo Transfer or had no information recorded, and percentage of positive and negative pregnancy test results. The data was formulated into a table, then into a graphical format to identify emerging trends and relationships.

AMH
0-1
1-2
2-3
3-4
4-5
Data in set
18
8
20
5
10
Avg age
40.7
42.5
39.9
40.6
43.4
Avg AMH
0.7
1.2
2.3
3.6
4.5
Avg start dose
477
506.3
405
480
366.7
Avg total dose
3875.5
3909.4
3453.8
4005
3250
Avg duration of stim
12.2
11.5
12
12.6
12.8
Ave no eggs
2.3
3.6
3.8
3.6
3.6
Avg embryos transferred
0.9
1.5
1.2
1.8
1.2
Abandoned cycles
9.1
0
0
20
10
No ET/failed fert
45.5
25.0
15
0
20
No information recorded
0.0
25.0
5
20
10
Positive test
18.2
0.0
25
40
20
Negative test
27.3
50.0
55
20
40
Pos test (of completed cycles)
40.0
0.0
31.3
66.7
33.3
Neg test (of completed cycles)
60
100.0
68.7
33.3
66.7



Findings from analysing data from IVF/ICSI cycles arranged and grouped in order of ascending AMH levels <5pmol/L are summarised below. A total of 61 cycles were analysed for women with an AMH of between 0 and 5pmol/L, however sample sizes between sub-groups varied significantly, with just 5 treatment cycles in the 3-4pmol/L group up to a maximum of 20 cycles included in the 2-3pmol/L group.

-         There was no correlation between mean age in ascending AMH groups between 0 and 5pmol/L.

-         Mean start dose and mean total dose of stimulation medication showed a minimal decreasing trend with increasing AMH values between 0 and 5pmol/L.

-         Mean number of eggs collected increased from 2.3 in the 0-1pmol/L AMH group to 3.6 in the 1-2pmol/L AMH group, and then remained static for the remaining AMH groups up to 5pmol/L.

-         As AMH increased, the number of cycles which did not proceed to ET consistently decreased from 45.5% in the 0-1pmol/L group to 0% in the 3-4pmolL AMH group. An anomaly was observed in the 4-5pmol/L AMH group as number of cycles which did not proceed to ET increased up to 20%. No trends were identified in the number of abandoned cycles or cycles which had no outcome information recorded between the AMH groups 0-5pmol/L.

-         A general increase in the proportion of positive pregnancy tests was observed across the ascending AMH groups. The best pregnancy rate was observed in the 3-4pmol/L AMH group with 40% positive test rate; the 1-2pmol/L groups had a 0% positive pregnancy test rate (however this subgroup consisted of a sample size of only eight treatment cycles).

These results, whilst still very interesting to explore, are overall fairly inconclusive in identifying strong correlations between factors, which may be attributed to the fact that the sample sizes in the sub groups were too small, or due to the fact that splitting cycles according to AMH intervals of just 1pmol/L is too small, and insufficient to distinguish adequate differences in outcomes between one group and the next. For example an AMH of 1.9pmol/L is insignificantly different to an AMH of 2.1pmol/L, which would be split into separate groups, where treatment outcomes may be approximated to be the same.





Age

All IVF/ICSI cycles included in the audit were subsequently ordered according to ascending maternal age, and grouped in 5 years intervals between 20 and 50 years. Data was summarised for each group on average age, average AMH, average start dose and total dose of stimulation, average duration of stimulation, average number of eggs collected and number of embryos transferred, percentage of cycles  which were abandoned/did not proceed to Embryo Transfer or had no information recorded, and percentage of positive and negative pregnancy test results. The data was formulated into a table, then into a graphical format to identify emerging trends and relationships.

Age
20-25
25-30
30-35
35-40
40-45
45-50
Data in set
6.0
16.0
58.0
76.0
42.0
21.0
Avg age
24.0
28.0
32.7
37.0
42.0
46.2
Avg AMH
29.0
31.0
23.4
15.0
8.0
5.8
Avg start dose
138.0
202.0
252.2
311.0
375.0
439.3
Avg total dose
1750.0
1753.0
2250.0
2731.0
3213.0
3939.3
Avg duration of stim
13.2
10.9
11.3
11.2
11.7
12.4
Ave no eggs
11.0
8.7
9.6
7.3
5.6
5.0
Avg embryos transferred
1.3
1.7
1.5
1.4
1.7
1.4
Abandoned cycles
0.0
0.0
1.7
7.9
2.4
4.8
No ET/failed fert
33.3
6.3
10.3
13.2
7.1
23.8
No information recorded
0.0
0.0
6.9
1.3
9.5
0.0
Positive test
33.3
56.3
36.2
31.6
21.4
19.0
Negative test
33.3
37.5
44.8
46.1
60.0
52.4
Pos test (of completed cycles)
50.0
60.0
44.7
40.7
26.5
26.7
Neg test (of completed cycles)
50.0
40.0
55.3
59.3
73.5
73.3



Findings from analysing data from IVF/ICSI cycles arranged and grouped in order of ascending maternal age are as follows:

-         Mean AMH decreased with ascending maternal age after the age of 30. Between the ages of 20 and 30, mean AMH was relatively static with a mean of 29.0pmol/L in the 20-25 years age group and a mean of 31.0pmol/L in the 25-30 years age group. This gradually declined to a mean of just 5.8pmol/L in the 45-50 years age group (of women who had IVF/ICSI treatment).

-         Mean start dose and mean total dose of stimulation medication increased with increasing maternal age values.

-         There was a general decrease in the mean number of eggs collected with ascending age groups.

-         As maternal age increased, there was a slight correlation with an increase in the number of abandoned cycles. However no significant correlation was identified with cycles which did not proceed to ET or cycles where no outcome information was recorded.

-         The proportion of positive pregnancy tests increased up to a peak of 56.3% in the 25-30 years age group (from 33.3% in the 20-25 years age group), after which point there was a consistent general trend of decreasing pregnancy rates, down to 19% in the 45-50 years age group.

The volume of data in each set should be factored into conclusions when considering the reliability of any average values. There were only 6 women in the 20-25years age group, which may account for slightly lower than expected pregnancy rates etc compared to other groups, compared to 16 in the 25-30years age group, 58 in the 30-35years age group, 76 in the 35-40 years age group, 42 in the 40-45 years age group, and 21 in the 45-50years age group. The vast majority of women were therefore aged between 30 and 45 years and average values are therefore likely to be more reliable for these age groups given the larger sample size.







IUI/IUDI/Follicle Tracking Treatment

Data in this group was insufficient to split into smaller groups as the sample size would be too small to make accurate estimations and draw conclusions. Included in the audit were 15 IUI/IUDI treatment cycles; 10 IUI cycles and 5 IUDI cycles. The average age of the women undergoing theses treatment cycles was 35 years, ranging from a minimum of 26 years to a maximum of 47 years. The average start dose of medication was calculated, to include women who were stimulated with gonadatrophins only (13 women), as no comparisons can be made between doses of alternate medications such as clomifene. The average start dose for the 13 women stimulated with gonadotrophins was 95IU, and the average total dose 835IU. The average duration of stimulation was 12 days. Out of the total 15 insemination cycles, 14 had outcome information recorded. This equated to a 7% positive pregnancy test rate across the 15 treatment cycles.



An additional five follicle tracking cycles were recorded in the audit, and one Ovulation Induction treatment cycle.  The average age of these 6 women was 40, and average AMH level was 37pmol/L, however they ranged vastly from 0.83 to 67.9pmol/L and the small sample size make these average values relatively arbitrary. No outcome information was recorded for 4 of the 6 cycles; the 2 cycles which had outcome information recorded both resulted in negative pregnancy test results. This highlights a need for better follow up of women having less intensive treatments such as simple Follicle Tracking or Ovulation Induction Cycles due to the high incidence of a lack of information in patients’ notes for these treatments compared to IUI/IVF/ICSI. No mean values could be calculated for start dose or total dose of ovarian stimulation as medications used varied too greatly between patients, with the use of clomifene, letrozole and menopur.

FET Treatment

From the 157 women included in the audit, there were 55 FET cycles recorded. As well as looking at overall success rates relating to FET cycles, data was broken down into the same groups as for IVF and ICSI and ordered according to ascending AMH and Age groups. This enabled an analysis of the proportion of women in each group who went on to have FET treatment following fresh IVF/ICSI cycles.

AMH

AMH
0-5
5-10
10-15
15-20
20-30
30-50
50+
Data in set
5
13
6
11
7
8
5
Avg age
37.4
39.5
39
34.1
33.9
36.1
31.4
Avg AMH
1.43
7.6
11.4
18
25.9
40.1
59.3
% natural cycles
60
38.5
66.7
72.7
57.1
25
40
% programmed cycles
40
61.5
33.3
27.3
42.9
75
60
Avg embryos transferred
1
2.2
1.8
1.5
2
2
2
Abandoned cycles
20.0
0.0
0
9.1
0
0
0
No ET/failed fert
20.0
0.0
0
9.1
0
0
0
No information recorded
0.0
0.0
16.7
9.1
0
12.5
0
Positive test
20.0
15.4
16.7
9.1
28.6
12.5
40
Pos test (of completed cycles)
33.0
15.4
20
12.5
28.6
14.3
40
No FETS as proportion of fresh cycles
9.3
23.2
24
32.4
30.4
50
33.3

No great imbalance was observed in regards to sample sizes across the different AMH groups, however most of the groups relatively small sized, ranging from a minimum of just five cycles  to a maximum of 13.

Findings from analysing data from Frozen Embryo Transfer cycles arranged and grouped in order of ascending AMH levels are as follows:

-         Mean age decreased across the increasing AMH groups in line with the trends identified from the fresh IVF/ICSI cycles.

-         There was a general decrease in number of abandoned cycles and those which did not proceed to Embryo Transfer with increasing AMH groups. No correlation was observed in cycles which had no outcome information recorded.

-         The percentage of positive pregnancy tests increased as AMH levels increased, with the highest proportion of positive pregnancy tests recorded in the AMH group 50+pmol/L at 40%.

-         There was a strong positive correlation linking an increase in the number of FET cycles as a proportion of fresh IVF/ICSI cycles in the same AMH subgroup. The proportion of FET cycles completed increased consistently across AMH groups up to a peak in the 30-50pmol/L group, therefore as AMH increased up to this parameter, so did the likelihood of women undergoing fresh IVF or ICSI cycles going on to have subsequent FET cycles. This may be attributed to the fact that as AMH increases, we expect women to achieve a higher number of eggs collected, and therefore they are more likely to have surplus embryos to freeze and use in subsequent Frozen treatment cycles.







Age

The age groups, categorised in 5 year intervals as for the fresh cycles, had variable sample sizes, with the two smallest groups consisting of results from 5 treatment cycles only and the two largest groups with a sample size of 18. This makes the comparison of mean parameters more difficult across the different age groups, as the groups with considerably larger sample sized are more likely to result in valid mean results, compared to less accurate, more easily skewed averages obtained from the groups with smaller sample sizes.

Age
<30
30-35
35-40
40-45
45-50
Data in set
5
18
18
7
7
Avg age
27.2
32.8
36.4
41.7
45.6
Avg AMH
26.4
21.3
23.8
12.1
10.7
% natural cycles
40
33.3
72.2
42.9
57.1
% programmed cycles
60
66.7
27.8
57.1
42.9
Avg embryos transferred
1.8
1.7
1.8
1.6
2.3
Abandoned cycles
0.0
11.1
0
0
0
No ET/failed fert
0.0
0.0
5.6
14.3
0
No information recorded
0.0
0.0
11.1
14.3
0
Positive test
20.0
33.3
11.1
0
14.3
Pos test (of completed cycles)
20.0
37.5
13.3
0
14.3
No FETS as proportion of fresh cycles
20.8
31.0
23.7
16.7
33.3



Findings from analysing data from Frozen Embryo Transfer cycles arranged and grouped in order of ascending age groups are as follows:

-         Mean AMH decreased with ascending age groups, as expected in line with predictions and trends observed from fresh IVF/ICSI cycles.

-         No correlations were observed with incomplete treatment cycles across the age groups.

-         It is apparent from the summary tables, that women in the 45-50 years age group had a higher average number of embryos replaced (a mean of 2.3 compared to means of 1.6-1.8 in all other age groups)

-         The proportion of positive pregnancy tests decreased with advancing maternal age, a peak of 33.3% was observed in the 30-35 years age group and a the minimum pregnancy rate was observed in the 40-45 years age group with a 0% positive test rate. However it is important to note that this group had a sample size of just seven cycles.





Conclusion

To conclude, the aim of the audit to identify emerging trends between patient AMH levels and fertility treatment outcomes has been met. The audit has succeeded in providing estimates of relative success rates for different patients according to their demographics. In this way women may be advised and given real estimates of likely treatment outcomes and success rates, based on outcomes of treatments conducted at the hospital for previous patients of a similar age or with similar AMH hormone levels.

A clear link between advancing age and depleting AMH levels was established from the audit, which reflects the theoretical basis. This is also reflected in the trends identified relating to an increase in the number of eggs collected with increasing AMH levels up to the 30-50pmol/L group, and decreasing numbers of eggs collected with advancing age groups. No significant trends or correlations were identified in the duration of stimulation across the different age groups or AMH groups.

Based on AMH levels alone, irrespective of the nature of fertility treatment women underwent, pregnancy rates increased up to a peak of 42.9% within the 20-25pmol/L group, beyond which point they began to gradually decline. Similarly, considering age alone, irrespective of treatment, pregnancy rates consistently decreased with advancing age groups, from a peak of 42.9% positive pregnancy tests in the 20-25 age group down to a minimum rate of a still very impressive14.7% positive pregnancy test rate in the 45-50 age group. It must be acknowledged that positive pregnancy test rates were above national averages in almost all categories.

Cycle abandonment rates and the proportion of cycles which did not proceed to Embryo Transfer decreased with increasing AMH levels up to the 30-50pmol/L group, beyond which point they increased dramatically, likely due to co-morbidities associated with high AMH levels >50pmol/L. The number of abandoned cycles and those that did not result in an Embryo transfer procedure also increased consistently with advancing maternal age groups.

For most categories, there was no significant correlation between the number of embryos transferred and maternal age or AMH levels, however in the Frozen Embryo Transfer cycles, women over 45 years were noted to have a higher mean number of embryos transferred, which reflect the HFEA guidelines and restrictions in place on how many embryos may be replaced for women dependent on their age. Women with higher AMH levels were increasingly likely to go on to have subsequent Frozen Embryo Transfer cycles after fresh IVF/ICSI, therefore increasing their chances of achieving a pregnancy and reflecting the fact that higher AMH levels and associated higher number of eggs collected increase the chances of having surplus embryos to freeze and ultimately increase the likelihood of a successive positive pregnancy test. No links were established to connect advancing female age and the likely success of FET treatment cycles.

Whilst the audit has been very useful in establishing correlations and summarising data to inform clinical staff and patients of the hospital, it has also highlighted a need for further research on this topic. Unfortunately, due to the broad range of characteristics of women included in the audit, when data was categorised and split into smaller groups based on the type of fertility treatment or age/AMH level parameters, some of the sub-groups had a very small data set and sample size. This resulted in some of the calculated averages being easily skewed by more extreme results and therefore results vary in accuracy/validity for this reason, which can affect the ability to establish real trends. By obtaining more results and ensuring groups have larger and more evenly distributed sample size, analysis and averages are likely to be more accurate. More research would also be beneficial to look at the ongoing pregnancy rates, which were not considered in this audit, due to the fact that not information of medical history or co-morbidities was gathered and multiple cycles and pregnancies are ongoing therefore results would be incomplete. The focus of this audit was on AMH levels and treatment outcomes, rather than on ongoing pregnancy rates. Due to the extensive data set that was collected, there is scope for further auditing to be conducted based on this information, with different visions and aims in mind.






References

The Association for Clinical Biochemistry and Laboratory Medicine, 2017. Anti-Mullerian Hormone. (online). Available from: https://labtestsonline.org.uk/tests/anti-mullerian-hormone

Human Fertilisation and Embryology Authority, 2018. Decisions to make about your embryos. (online). Available from: https://www.hfea.gov.uk/treatments/explore-all-treatments/decisions-to-make-about-your-embryos/


Vol.16, JUNE 2020, Recurrent IVF failure: What to Do

Recurrent IVF Failure - What to Do Mr J. Adeghe PhD, FRCOG.,  Consultant – Fertility & Gynaecology St Jude Hospitals & Clinics, ...