The decline in fertility as we age is almost entirely a result of the decline in egg quantity and quality. We know this because older women who use donor eggs have pregnancy rates similar to younger women. But what does egg quality mean? Broadly, it describes the potential of an egg to become a viable pregnancy after fertilization. And this is no trivial matter – the vast majority of fertilized eggs simply do not have what it takes.
Egg Quality Is Everything
For any embryo, the first few weeks after fertilization represent a major hurdle, and many embryos stop developing at some point during this time. In fact, most naturally conceived embryos are lost before a woman even knows she is pregnant. Only about a third of fertilized embryos actually survive to become a baby. The odds may be even worse in the IVF context, where many fertilized eggs are unable to progress to the five-day embryo stage (known as the “blastocyst” stage), and those that do make it to this stage and are transferred to the uterus often do not successfully implant, resulting in a failed IVF cycle.
The fact that most fertilized eggs never become a successful pregnancy is an issue that receives very little attention because there is a common misconception that getting an egg fertilized is the real challenge in conceiving. Most natural fertility advice therefore focuses on ovulation and timing to achieve fertilization. This approach misses the mark because the potential of a fertilized egg to continue developing is often a much bigger issue. In reality, egg quality plays a critical role in how long it takes to become pregnant, whether naturally or through IVF, and the secret is in the egg’s DNA.
Although an embryo’s potential to develop into a pregnancy depends on many factors, by far the most important is having the correct number of copies of each chromosome. Chromosomal abnormalities in eggs have a profound impact on fertility because at every stage of development from fertilization onward, an embryo formed from a chromosomally abnormal egg has much less potential to continue developing. This may manifest as an inability to get pregnant or as early miscarriage. For many women, chromosomal abnormalities in eggs become the greatest obstacle to conceiving and carrying to term.
It comes as no surprise that poor egg quality is significantly more common in women who have had a difficult time conceiving. High rates of chromosomal abnormalities are seen in eggs of women who have a history of multiple miscarriages, women who have had repeated IVF cycles in which embryos were transferred but no pregnancy occurred (so-called “repeated implantation failure”), and women with polycystic ovary syndrome. For example, the proportion of abnormal embryos in women with a history of repeated implantation failures in IVF cycles can be up to 70%.
Chromosomal errors in eggs not only impact the ability to get pregnant but are also a major cause of miscarriage. Miscarriages are unfortunately very common, occurring in about 10–15% of recognized pregnancies. However, most pregnancy losses are not even noticed because they happen so early – before the woman knows she is pregnant. When such pregnancies are taken into account, up to 70% end in miscarriage. Part of the reason for this incredibly high rate is that from the moment of conception, a continuous process of selection against chromosomally abnormal embryos is taking place.
In fact, chromosomal abnormalities cause more miscarriages than every other known cause of miscarriage combined. In one study in Japan involving almost 500 women with a history of 2 or more miscarriages, 41% of miscarriages were found to be caused by a chromosomal abnormality in the fetus, whereas all the other known causes of miscarriage together accounted for less than 30% of pregnancy losses. Other studies have found that more than half of all first-trimester miscarriages are caused by chromosomal abnormalities. It is also important to note that these studies were investigating miscarriages from recognized pregnancies only, and the rate of chromosomal abnormalities is likely to be much higher for losses that occur in the short time after fertilization.
A common reaction to this information is that chromosomal errors in eggs are beyond our control, but recent scientific research is showing that is not true. The proportion of eggs with chromosomal abnormalities can be influenced by nutrients and lifestyle factors you can control. As will be discussed later in this chapter, research suggests that one-way external factors can influence egg quality is by boosting or compromising the egg’s potential to produce energy at critical times – energy that provides the fuel for proper chromosome processing.
The best-known example of a chromosomal abnormality originating in the egg is Down syndrome, which becomes much more common as women age and egg quality declines. In 95% of cases, Down syndrome is caused by the egg providing an extra copy of chromosome 21, which results in the fetus having three copies instead of the usual two. For this reason, Down syndrome is also called Trisomy 21.
Down syndrome is just one example of a chromosomal abnormality, but it is perhaps the best known because it is one of the few in which the affected fetus can survive to term. Some babies with Trisomy 13 or Trisomy 18 (an extra copy of chromosome 13 or 18) can also survive to term, but with life-threatening medical problems. An extra copy of other chromosomes will prevent the embryo from developing past the first few days or weeks, or will cause an early miscarriage. This is why we rarely hear about chromosomal errors involving extra copies of these other chromosomes, even though they are very common.
While having an extra copy of a chromosome is the most common type of chromosomal abnormality, occasionally a missing chromosome or more complex errors can also occur.
An egg with the incorrect number of chromosomes is called “aneuploid.” An embryo created from one of these aneuploid eggs will also be aneuploid and will have very little potential to successfully implant in the uterus. Even when aneuploid embryos are able to progress to a pregnancy, the vast majority of such pregnancies end in an early miscarriage.
In women over 40, more than half of eggs may be chromosomally abnormal. In fact, by some measures, the rate of abnormalities in women over 40 is as high as 70–80%. Studying chromosomal abnormalities in eggs, we see an exponential increase in the fertility challenge faced with age, starting in the mid- to late 30s. But egg quality has an impact in all age groups, and chromosomal errors in younger women are much more common than you might expect.
Even in women under 35, up to a quarter of eggs are aneuploid on average. This means that if you are a young, healthy woman without any fertility issues, there will still be many ovulation cycles in which you have little potential to conceive. If the egg that you ovulate in a given month is chromosomally abnormal and unable to support a pregnancy, using ovulation prediction kits and charts to achieve fertilization with perfect timing will not make any difference; you will probably not be able to conceive until the next cycle in which you ovulate a good egg.
The dramatic impact of chromosomal abnormalities on the chance of conceiving and carrying to term is particularly apparent in the IVF context. If this factor is taken out of the equation, the pregnancy rates skyrocket. We know this from an exciting new approach to IVF in which embryos are first screened for abnormalities in every chromosome, and only the normal embryos are transferred.
This is very different from the traditional measure of “embryo quality” in the IVF context, which is based on the growth rate and overall appearance of the embryo. A slow-growing embryo with irregular-looking cells is less likely to lead to a pregnancy, but it has become clear in recent years that assessment of embryo quality based on appearance or “morphology” is no guarantee. What matters much more is screening for embryos that have normal chromosomes.
When comprehensive chromosome screening was introduced for poor-prognosis patients, the difference was dramatic. Instead of the usual 13% of transferred embryos successfully implanting for patients 41–42 years old, selecting only chromosomally normal embryos boosted the implantation rate to 38%. As a result, the proportion of women in this age group completing an IVF cycle who actually took home a baby doubled.
While chromosomal screening represents a very significant advance, it is not a cure-all. One of the main problems is that screening may show that none of the embryos created in an IVF cycle are chromosomally normal. As a result, there will be no good embryo available to transfer. This happened to about a third of patients in one study, demonstrating that egg quality will still remain a limiting factor to becoming pregnant, even with new screening methods.
Yet chromosomal screening does hold great promise and shows the dramatic impact of egg and embryo quality on pregnancy rates. Interestingly, this impact is not limited to “poor-prognosis patients.” A group in Japan set out to determine how much they could improve pregnancy rates in IVF cycles by choosing to transfer only chromosomally normal embryos, but this time they were looking at women under 35 with a good prognosis and no previous miscarriages. In the control group, in which embryos were chosen by appearance alone, 41% of patients became pregnant per IVF cycle and carried to at least 20 weeks. In the group in which embryos were chosen by chromosomal screening, the pregnancy rate jumped to 69%. The miscarriage rates were also very different: 9% in the control group and just 2.6% in the screened group.
The lesson we can take away from the positive results of chromosomal screening is that having a chromosomally normal embryo has a huge impact on the chance of a successful pregnancy, no matter how you are trying to conceive. Even if trying to conceive naturally, your chance of becoming pregnant and carrying to term is very much determined by your egg quality. Luckily, egg quality is not entirely predetermined by your age or fixed in time. It can change.
There is, in fact, an enormous variation in chromosomal abnormality rates between different women of the same age. One 35-year-old may ovulate very few chromosomally normal eggs over a given time frame, while another woman’s eggs may all be normal at the same age. This was shown in a study of IVF patients in Germany and Italy in which the percentage of chromosomally normal eggs ranged greatly between different women of the same age. The number of normal eggs also varied widely over time for each woman, which was seen as a significant difference in the proportion of normal eggs between two consecutive IVF cycles. The researchers described the variation over time and between different women as random and unpredictable, but only because they did not connect their research to the many other studies showing specific influences on the rates of chromosomal abnormalities. The fascinating research discussed in the remainder of this book establishes that this variability is not purely random; on the contrary, a wide range of external factors impact egg quality.
Countless clinical studies have shown that avoiding certain toxins and adding specific supplements can increase the percentage of eggs that can develop into a good-quality embryo, increase the percentage of embryos that implant in the uterus, and reduce the risk of early-pregnancy loss. There is strong scientific evidence that some of these improvements are due to a reduction in the proportion of eggs with chromosomal abnormalities, confirming the fact that egg quality is something we have the power to change.
How Do Eggs Become “Chromosomally Abnormal”?
The process of egg production is very long and error-prone. The development of each egg begins before a woman is even born, in the newly forming ovaries during the first trimester of pregnancy. A girl is born with all the eggs she will ever have, and each egg exists in a state of suspended animation until a few months before ovulation.
Approximately four months before ovulation, a small pool of immature eggs begin to grow, and while most will die off naturally, one lead egg is selected from the pool to finish maturing. The fully-grown egg completes ovulation by bursting from its follicle and traveling down the fallopian tube, ready to be fertilized.
During the decades-long interval between early egg development and ovulation, eggs have many opportunities to accumulate damage as a part of normal aging. The traditional belief is that by the time a woman is 40, her eggs have already accumulated chromosomal abnormalities, and nothing can be done to change that. But that is not scientifically correct, because most chromosomal errors actually occur shortly before ovulation, in later stages of a process called “meiosis.”
An egg ends up with the incorrect number of chromosomes when meiosis goes awry. Meiosis involves carefully aligning chromosome copies along the middle of the egg, then pulling one set to each end of the egg with a network of microscopic tubules. One set of chromosomes is then pushed out of the egg in what is called a “polar body.” A developing egg actually does this twice – it starts out with four copies of each chromosome and, if the process goes correctly, ends up with just one copy of each chromosome.
If this process fails at any stage, the end result is an extra or missing copy of a chromosome. Although the first round of meiosis begins before a girl is born, most of the chromosomal processing activity happens in the months immediately before an egg is ovulated.
The critical point to note – and a point that many fertility doctors are not aware of – is that most of the chromosomal abnormalities in eggs do not accumulate gradually over 30 or 40 years as an egg ages, but instead happen in the couple of months before an egg is ovulated. In other words, aging does not directly cause chromosomal abnormalities; rather, it creates conditions that predispose eggs to mature incorrectly shortly before ovulation.
This means that by changing those conditions before ovulation, you can increase the odds of an egg maturing with the correct number of chromosomes. In short, you may be able to influence the quality of eggs that you ovulate a couple of months from now because chromosomal errors in those eggs have probably not occurred yet.
This leads us to the fundamental issue: How can an egg be predisposed to mature with an incorrect number of chromosomes, and what can you do about it? Every chapter in this book addresses different aspects of that question, but a common theme is the egg’s energy supply.
Energy Production in the Egg
It takes an enormous amount of energy for the egg to process chromosomes correctly and do all the other work necessary to mature properly. It turns out that the energy-producing structures inside eggs change significantly with age and in response to nutrients and other external factors. These structures, called “mitochondria,” are found in nearly every cell in the body. They act as miniature power plants to transform various fuel sources into energy that the cell can use, in the form of ATP.
ATP is quite literally the energy of life. It moves muscles, makes enzymes work, and powers nerve impulses. Just about every other biological process depends on it. And it is the primary form of energy used by eggs. A growing egg needs a lot of ATP and has a lot of mitochondria. In fact, each egg has more than fifteen thousand mitochondria – over ten times more than any other cell in the body. The follicle cells surrounding the egg also contain many mitochondria and supply the egg with additional ATP. But these mitochondria must be in good condition to make enough energy.
Over time, and in response to oxidative stress, mitochondria become damaged and less able to produce energy. Without sufficient energy, egg and embryo development may go awry or stop altogether. A growing body of evidence suggests that the ability of an egg to produce energy when needed is critically important to being able to mature with the correct number of chromosomes. It is also vital to an embryo’s potential to survive the first week and successfully implant.
Poorly functioning mitochondria may be one of the most important reasons some women’s eggs are more likely to end up with chromosomal abnormalities or otherwise lack the potential to become a viable embryo. What you can do to help “recharge” your mitochondria and thereby boost your eggs’ energy supply is the subject of several chapters later in this book, but first we turn to another contributor to chromosomal errors in developing eggs – the toxin BPA.