ART Techniques for Women of Advanced Maternal Age (+38)

Elias Tsakos MD, FRCOG
Medical Director , Embryoclinic

Advanced Maternal Age

From this video you will find out:
  • How does age impact a woman’s fertility and her chances of getting pregnant naturally?
  • Are there any factors that can influence the success of ART in older women?
  • What are the potential risks and considerations for women of advanced maternal age who undergo ART procedures?
  • What can women do to optimize their health and increase their chances of success with ART before conception?
  • Are there specific lifestyle changes or medical interventions that can improve outcomes for older mothers?

ART Techniques for Women of Advanced Maternal Age (+38)

Dr Elias Tsakos, Fertility Expert and Medical Director of Embryoclinic, discussed and explained the latest advancements in Assisted Reproductive Technology tailored to women over 38.

Defining Advanced Reproductive Age

In most scientific textbooks and journals, we find that 35 years and older is the beginning of the definition of advanced reproductive age. However, the average age of female patients seeking fertility treatments is just under 39 (38.8 years). So, we know that after the age of 35, the chances of conception decrease, affecting both natural fertility and assisted reproductive techniques. Additionally, there is an associated risk of adverse outcomes.

Why is advanced maternal age an issue? One crucial aspect is genetic anomalies, with the chance of genetic anomalies leading to either failure, miscarriage, or abnormality being more likely as fertility diminishes. This affects not only the quantity but also the quality of eggs. There is also an increased maternal risk due to factors associated with age, including uterine pathology, infections, cervical anomalies, and general medical conditions like diabetes, hypertension, and obesity.

As for the ovaries, there is a reduced ovarian reserve, with the quality and function of eggs diminishing with advanced age. This decline begins in the late 20s, accelerates around the age of 35, and decreases further after the age of 40, nearly disappearing after 45.

It’s essential to understand that the reduction in fertility applies to natural and assisted fertility, and IVF success rates primarily depend on the female’s age. There is also an increased risk of miscarriage in this age group, which may be due to a combination of factors.

General health concerns are significant, especially in preconception care, where we need to assess and counsel women wishing to become pregnant. These concerns include a higher chance of malignancy, cardiovascular risks, metabolic syndrome risks, and thrombotic risk, which can be associated with factors like hormonal stimulation and pregnancy. Screening for cervical pathology and HPV testing is also crucial.

In summary, just as you wouldn’t start a journey across Europe in your car without a comprehensive service, it’s unwise to embark on a fertility journey without a thorough assessment of all potential risk factors. These factors can affect not only the success or failure of IVF but also the success or failure of pregnancy and a woman’s general health and well-being. This applies to uterine dysfunction, fibroids, adenomyosis, endometriosis, and uterine polyps. The uterus must be in perfect condition, not only for successful fertility but also for the woman’s health, as we occasionally diagnose cases of uterine cancer, which underscores its importance.

The impact of age on female fertility

The more advanced the female’s age, the more likely it is that we may find something important. Equally, it may be important for success. There are conflicting reports in the literature. In 2023, the majority of women undergo IVF without a formal assessment of the uterine cavity or the fallopian tubes. Not all fibroids need removal, however, the uterine cavity, at least the endometrium, has to be evaluated. Even when there’s no suspicion from the scan, roughly 20% of small polyps are not visible on scans, even in the best hands. They need to be addressed, treated, and sorted out with a biopsy before proceeding.

Obstetric teams are improving, but all pregnancy complications are much higher with advanced maternal age.

I can’t stress enough the value and importance of single embryo transfer, especially after the age of 40, where the chances of complications increase.

Primary fertility treatment options

The journey begins with fertility treatment and pre-IVF testing. It’s essential to assess and optimize before embarking on the treatment. There’s a wide range of options, including IVF, ICSI, embryo donation, and even gestational surrogacy in specific cases. Genetic testing is also crucial in the assessment. Pre-IVF testing is vital. It includes basic testing and more advanced tests. Microbiome assessment may be necessary, especially in cases of repeated unexplained failures. Genetic testing is essential, but the depth of testing varies depending on the complexity of the case.

Pre-IVF testing starts with basic assessments and progresses as the case becomes more complex. In some cases, endometrial platelet-rich plasma (PRP) may be beneficial, particularly for women with advanced reproductive age, implantation failures, miscarriages, or adhesions. Sperm quality should not be overlooked. The assessment of male infertility is a growing field, and it’s essential to explore sperm quality comprehensively.

Treatment options

There is an egg donation option, embryo donation but also surrogacy. Surrogacy is usually the last resort. If you’ve tried everything, or there are factors like malignancy, Rokitansky syndrome, multiple fibroids, or hysterectomy, there’s no chance of carrying your own baby. There is also a new method like uterus transplantation which is also gaining recognition. More reports are emerging from around the world, and it seems that Europe, especially the Swedish team, leads in this field. Uterus transplantation may become a more viable option for patients worldwide in the next 3 to 5 years, before or alongside surrogacy.

Supplementary options include pre-genetic testing, PRP for rejuvenation, hysteroscopy, and robotic surgery. The efficacy of PRP is still being explored, especially in identifying which subgroups of patients might benefit. Hysteroscopy seems helpful, especially for women of advanced reproductive age. Robotic surgery, which has been around for over 20 years, is here to stay. There is less chance of conversion to laparotomy, reduced blood loss, and improved outcomes.


In conclusion, advanced reproductive age is becoming more common in assisted reproduction. Women of advanced age face poorer fertility outcomes and a higher risk of adverse events. Therefore, it’s crucial to provide comprehensive counseling and pre-fertility testing. There are multiple options available, and the choice depends on individual indications. Additionally, there are various supplementary methods to improve outcomes.

Related reading:

- Questions and Answers

What kind of simulation protocol do you recommend for older women with PCOS? Do you use Clomid or Femara? I’m 51, but my FSH is still 5.6 nanograms per millimeter, LH is 4.4, prolactin is 64.4, estral is 111.6, and I don’t have high testosterone. My last AFC was 26. I get a lot of eggs with FSH-only protocols, but they are immature. Last round I did estrogen priming and added LH to the protocol, but got only four eggs, two of them fertilized, and only one blastocyst. 

To be honest, I have no experience of stimulating anyone in your age group, so I don’t know. The oldest woman in the literature who conceived after IVF with her own eggs has been 46. I’ve discussed this with my colleagues, but no one has published cases of success in your age group. I would be very sceptical of stimulating someone in your age group. I would consider PGT-A because the chance of producing a chromosomally healthy blastocyst may be very low. I’m sorry I can’t help you specifically, but you’re a fascinating case. For older women with PCOS, the choice of simulation protocol would depend on several factors. Plummets or Femara could be considered, but it’s important to consult with a reproductive specialist for a personalized recommendation. Your hormonal profile is unique, and stimulating someone in your age group comes with challenges. It’s advisable to consult with a fertility specialist who can assess your situation and provide tailored advice.

What grade of cervical pathology would be acceptable for IVF? What about HPV? Is it possible to go through IVF with a positive HPV result?

The acceptability of cervical pathology and HPV status for IVF depends on various factors. It’s crucial to consult with a gynaecologist and oncology team for a proper assessment and management plan, considering colposcopy, HPV testing, and potential follow-up.

What to do if factor VIII (only this one) is above the norm, and doctors say it’s not a mandatory sign for thrombophilia?

Managing factor VIII levels above the norm in the context of thrombophilia is complex and depends on various factors, including age and overall health. Consult with a hematologist and a fertility specialist to make informed decisions regarding your specific case.

In my hysteroscopy, there was a possibility of adhesions but not certainty. At the same time, my endometrium is always between 7-11 mm at the moment of ovulation. Does such an endometrium exclude adhesions in your opinion? Can adhesions prevent implantation? From your experience, how big is the improvement achieved by PRP? I’m 41 but already at age 36, my testosterone was practically zero. How many failed IVF cycles are too many? I’ve had several complete fertilization failures and empty follicles. I’ve had 8 already, all with high stimulation doses.

To be honest, I’m a little bit concerned about the variability between 7 and 11 mm. Adhesions are usually either present or absent. If there’s any doubt about adhesions, it’s essential to reassess through hysteroscopy. If you have any images or videos of the hysteroscopy, it would be helpful for a more accurate evaluation. If in doubt, a repeat hysteroscopy may be necessary. I have no personal experience with PRP (platelet-rich plasma) in fertility treatments. The evidence is not very sound, and I recommend caution when considering such treatments. It’s crucial to inform patients about the limited evidence and potential outcomes. The number of failed IVF cycles depends on various factors. If you’ve experienced multiple failures with high stimulation doses, it might be time to consider alternative approaches, such as mild stimulation or natural cycles. If those don’t work, egg donation could be an option. It’s important not to use the same approach repeatedly without success.

What would you suggest for recurrent implantation failure? I’ve had a biopsy, laparoscopy, ERA, thrombophilia and thyroid tests done. A total of 40 embryo transfers, four PGT-tested embryos, two blastocysts, and 41 trying since I was 34. 4 clinics in 3 countries.

For recurrent implantation failure, it’s essential to explore various factors, including hysteroscopy, laparoscopy, thrombophilia, thyroid, and sperm evaluation. ERA testing may not be supported by current evidence. PGT testing could be beneficial if embryos are produced. The choice of stimulation protocol and individualized care is crucial. Keep trying if you produce embryos, but also consider alternative approaches and stay healthy.  

What is the impact of BMI on the IVF protocol? Does the medication get more diluted, making it less effective in terms of stimulation?

Yes, BMI can impact the IVF protocol. Medication dosage is often based on a per-kilogram basis, and BMI can affect the required dosage. Different protocols and compositions may be needed based on the patient’s weight and other factors.

If you have had a hysteroscopy previously, do you need to repeat it if it was done 8-10 years ago and you’ve had multiple IVF attempts since then?

It’s advisable to repeat a hysteroscopy, especially if you’re over 40 and have had multiple IVF attempts. This will help ensure that there are no new issues or changes in the uterus since your previous hysteroscopy.

What about the treatment of Ureaplasma found in a random culture of asymptomatic vaginal smear? Should we treat it?

Ureaplasma treatment is recommended, but retesting may not be necessary as long as the treatment is effective. Ureaplasma may not be as concerning as it was once thought to be, but treatment can be beneficial for fertility.

I have high thyroid antibodies and my thyroid function blood test is within the normal range. How should this be approached before or during IVF?

High thyroid antibodies with thyroid function within the normal range may require a small dose of thyroxin, especially for women aiming for pregnancy. Regular monitoring and maintaining TSH levels within an optimal range are important.

I’ve had two rounds of stimulation with low follicle counts. I’m 41 and have stage 4 endometriosis. Should the stimulation protocol be changed?

Your response to stimulation is not necessarily low for your age and condition. Focus on addressing endometriosis and Crohn’s disease. Keep using the protocol that produces the most follicles, and consider addressing any factors that might have affected egg fertilization. It’s essential to address your medical conditions and have another attempt.
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Hysteroscopy before IVF:  can it improve outcomes?
Recurrent Pregnancy Loss challenges: causes and solutions
How to prepare for an embryo transfer to improve your chances: There’s more to consider than just the endometrium
Endometrial factor and recurrent failures in IVF: diagnosis and treatment
How old is too old for my IVF treatment?
Elias Tsakos MD, FRCOG

Elias Tsakos MD, FRCOG

Dr Elias Tsakos, FRCOG, is a Medical Director of Embryoclinic - Assisted Reproduction Clinic in Thessaloniki, Greece. He has received extensive and certified training in the United Kingdom and is a Fellow of the Royal College of Obstetrics & Gynaecology. Dr Tsakos is also a Board Member Representative of the Royal College for Greece and Cyprus and a Board Member of the Hellenic Society of Assisted Reproduction. He is a Member of the British, European and American Fertility Societies (BFS, ESHRE, ASRM). Dr Tsakos has been living and working in Thessaloniki, Greece, since 1999.
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Caroline Kulczycka

Caroline Kulczycka

Caroline Kulczycka is managing MyIVFAnswers.com and has been hosting IVFWEBINARS dedicated to patients struggling with infertility since 2020. She's highly motivated and believes that educating patients so that they can make informed decisions is essential in their IVF journey. In the past, she has been working as an International Patient Coordinator, where she was helping and directing patients on their right path. She also worked in the tourism industry, and dealt with international customers on a daily basis, including working abroad. In her free time, you’ll find her travelling, biking, learning new things, or spending time outdoors.
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