Advanced Maternal Age

Nowadays it is more and more common for women to decide on a pregnancy later in life.  It happens so due to social and cultural changes related to, among others, education, career, financial stability or simply meeting the right person to start up a family with. Sadly, often the deciding actor is also the struggle of previous unsuccessful fertility treatments over the course of many years. 

But although social preferences in the world might be changing, the woman’s fertility isn’t. The fact that women choose the path of motherhood later on, does have its serious implications and consequences. It is difficult to synchronise the body with modern lifestyle as it is the age of a woman that plays the most important role in conception. Oocyte quality and quantity are known to diminish with age, making it less probable for a woman to conceive and then carry a child to term. And if a woman of advanced maternal age does get pregnant, there is a significantly higher risk of adverse pregnancy outcomes such as, e.g., pre-eclampsia, low birth rate, congenital birth defects and chromosomal anomalies.

The definition

Advanced Maternal Age (AMA) is generally defined as the age above 35 years. However, because of the mentioned social and cultural changes, the upper limit for AMA is more and more often determined as the age of 40. Additionally, thanks to the access to assisted reproductive technology (ART) and IVF, there have also been new definitions created – Very Advanced Maternal Age (VAMA) and Extremely Advanced Maternal Age (EAMA), describing women delivering at the age of 45-49 and even over 50.

The biology

Women are born with a limited number of eggs and over time, the quality and quantity of these eggs (the so-called ovarian reserve) decrease. On average, during the fourth month of fetal development, females have between 6 to 7 million oocytes. A rapid loss of eggs is experienced at birth, when the total number decreases to between 1 to 2 million (and is classed as 100% of woman’s oocytes). When a girl reaches her first menstruation takes place, the number of oocytes drops to around 300,000 – 400,000. This further reduces to 180,000 at the age of 30, and then again to 45,000 around the 40-year mark. As a woman heads towards the menopause, the number of her eggs is continuously diminishing.

The risks

As women age, the number and quality of their eggs are declining and their fertility is being reduced.  Studies show that when a woman is in her 20s, she has a 20% chance for getting pregnant each month. However, this chance is reduced to only 5% in her 40s. In addition, when a woman is in her 40s, her aging eggs ( and – as a result – embryos made from those eggs) are more likely to contain chromosomal abnormalities – aneuploidies. An aneuploidy is the presence of an abnormal number of chromosomes in a cell – this abnormal number is known to be a factor in embryonic developmental abnormalities. It is estimated that in women over 42, over 85% of embryos will have aneuploidies. The most common example of a chromosomal aneuploidy is Down syndrome (trisomy 21) which involves an extra chromosome 21. The risk of a Down syndrome in patients who are older than 35 years old is 3.5 times greater than in somebody who is 23 years old. 

Pregnancies with chromosomally abnormal embryos are more likely to result in a miscarriage. In addition, as a woman ages, it is more probable that she will have uterine fibroids and endometrial polyps that could also be a serious factor affecting fertility.

The treatment 

If a woman over 35 years old is trying to get pregnant unsuccessfully for 6 months, she is advised to visit a fertility specialist. The treatment process will be usually started by completing an assessment of her ovarian reserve. It includes antral follicle count (used to determine the sum of follicles in both ovaries) and AMH (Anti-Mullerian Hormone) which level in a woman’s blood is a good indicator of her ovarian reserve. Afterwards, a woman will usually be recommended possible treatment options for advanced maternal age, including in-vitro fertilisation (IVF), IVF with PGS (preimplantation genetic screening) and IVF with donor eggs.  

As it is known that women are designed to generate chromosomally normal embryos until they are 35, IVF with own eggs may be no longer effective in women who are 40 years old and more. In fact, the pregnancy rate in women, who are over 35 years old and do not undergo the genetic testing of their embryos, is only about 20%. But with modern technology that allows for the preimplantation genetic screening of embryos (PGS), doctors nowadays are able to define chromosomal abnormalities in embryos (such as, e.g., Down’s syndrome, Edwards’ syndrome or Patau’s syndrome) and select only the healthy ones. Genetically normal embryos may then be frozen by the vitrification method. Thanks to it, a patient can have her embryos transferred at convenient time in her life. The solution, called embryo banking, is offered to patients who generate good-looking embryos that are graded either A (excellent) or B (good) quality but have low AMH.

Unfortunately, healthy embryos are not always possible to be found. If IVF with PGS has turned unsuccessful in case of a patient of advanced maternal age, egg donation might be the only remaining and pragmatic solution. IVF with donor eggs involves using eggs from a younger egg donor. The donor eggs are fertilised in a laboratory using the sperm of the patient’s partner. At the same time, the patient is given hormone therapy to prepare her uterus to carry the embryos. After fertilisation, the embryos are transferred into the patient’s uterus. In this way, it is possible to bring an over 40-year old female patient to the pregnancy rates of a woman who is 20 years old. The pregnancy rates in egg donation are quite impressing. Generally, after one embryo transfer, 70% of patients are found pregnant, after 2 transfers – 90%, and after 3 transfers – even up to 97%.

The conclusion 

Fertility treatment of advanced-age patients depends on various and specific factors. It is important to remember that every patient is different and her case is individual. Each woman may have a differing number of oocytes (of varying quality) and not all fertility clinics and fertility specialists agree on exactly the same treatment strategies. But no matter what kind of treatment protocol clinics decide to use, they must always remember that each woman is unique. Personalised approach tailored to the individual patient, based on her own predispositions and medical history, is crucial to optimise reproductive outcomes.