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Female Age and Chromosomal Abnormalities (Aneuploidy) in Eggs and Embryos

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The main reason for the increased risk for miscarriage in "older" women is due to the increase in chromosomal abnormalities in their eggs.

There are 2 general types of chromosomal abnormalities:
  • Numerical abnormalities where there is an abnormal number of chromosomes
    • This situation is called aneuploidy
    • Such as a missing (monosomy) or an extra chromosome (trisomy)
    • An example of monosomy is Turner Syndrome and a well known example of trisomy is Down Syndrome
  • Structural abnormalities where there is a problem with the structure of a chromosome
    • Examples include translocations, duplications and deletions of part of a chromosome

Aneuploid eggs and embryos are also responsible for most of the decline in overall fertility with female aging - and for the low pregnancy success rates with IVF for women over 40.

The increased rate of chromosomal abnormalities in women of advanced reproductive age has been well documented in research studies. The graph below shows the rate of chromosomally abnormal IVF eggs by female age. These numbers are approximate and compiled from several studies.

Rate of chromosomally abnormal human eggs

Chromosomal Problems in Aging Eggs

We do not know exactly why there is an increase in chromosomal abnormalities in the eggs of women as they age. However, research studies have clarified some of the issues involved.

The meiotic spindle is a critical component of eggs that is involved in organizing the chromosome pairs so that a proper division of the pairs can occur as the egg is developing. An abnormal spindle can predispose to development of chromosomally abnormal eggs.

Study on Human Egg Spindles and Female Age

An excellent study published in the medical journal "Human Reproduction" in October of 1996 investigated the influence of maternal age on meiotic spindle assembly in human eggs.

  • This study gives insight into how chromosomally abnormal eggs (and therefore, embryos) are more common in older women.
  • 17% of the eggs studied from women 20-25 years old were found to have an abnormal spindle appearance and at least one chromosome displaced from proper alignment.
  • 79% of the eggs studied from women 40-45 years old were found to have an abnormal spindle appearance and at least one chromosome displaced from proper alignment.

The pictures below are from this journal article. These photos were taken with confocal fluorescence microscopy of eggs stained with special dyes to show the spindles and chromosomes.

  • The orange spots are pairs of chromosomes in the eggs.
  • The green area is the spindle apparatus.

egg chromosomes in young woman disorganized spindle from older egg
Chromosomally Normal Egg
Egg from a woman in her 20's
Chromosomes line up straight on spindle
Chromosomally Abnormal Egg
Egg from a woman in her early 40's
Chromosomes line up erratically - a mishap during chromosome separation is much more likely

When the chromosomes line up properly in a straight line on the spindle apparatus in the egg, the division process would be expected to proceed normally so that the egg would end up with its proper complement of 23 chromosomes.

However, with a disordered arrangement on an abnormal spindle, the division process may be uneven - resulting in an unbalanced chromosomal situation in the egg.

Older eggs are significantly more likely to have abnormally functioning spindles - which causes an increased rate of chromosomal problems in the mature eggs.


Why do some women have more chromosomally abnormal eggs than average for their age?

  • Insight from a study about a gene that regulates normal egg development (in mice)

In August 2009 a study was published (article by Lelanda referenced below) showing that mice that had a mutation in a specific gene had significantly higher rate of chromosomal abnormalities than normal.

  • The gene is called Bub1
  • The gene is involved in regulation of the proper division of pairs of chromosomes during the egg maturation process
  • The degree of the chromosomal problems were found to increase with maternal age
  • The chromosomal abnormalities were passed on to the embryos and resulted in high rates of loss after implantation
  • It is not yet known how often a gene mutation like this might cause similar problems with human reproduction
    • You might think we are very different from mice - but we are not (sorry about that)

This study is very interesting and could give insight into reasons for some women having infertility, recurrent IVF failure, or recurrent miscarriages.

  • Similar research needs to be done in humans
  • In the future we could possibly have a blood test (genetic testing) that could predict risks for chromosomal problems in a woman's eggs and embryos.

Chromosomal Errors in Eggs Causing Down Syndrome

Screening tests are available that can help to assess the risk that a fetus has Down syndrome.

In the first trimester of pregnancy, screening can be done using:

  • Blood tests on the mother looking at biochemical markers
  • Ultrasound measurement of nuchal translucency (fluid collection at the back
    of the fetal neck)
  • Using a combination of these 2 methods is more effective as first trimester screening

In the second trimester of pregnancy, screening can be done using:

  • Triple screen (70% of Down syndrome pregnancies will be positive)
    • Alpha-fetoprotein (AFP), unconjugated estriol (uE3) and hCG
  • Quadruple screen (80% of Down syndrome pregnancies will be positive)
    • Same as triple screen + inhibin A
  • Ultrasound

When screening tests show an increased risk for a chromosomal problem in the baby the couple should be offered genetic counseling and the option of chorionic villus sampling CVS or amniocentesis.

  • CVS is done in the late first trimester (usually between 11 and 12 weeks) and involves a biopsy of the placenta to determine the baby's chromosomes.
  • Amniocentesis is usually done at about 16 to 18 weeks pregnancy (second trimester) and involves aspirating some amniotic fluid from the sac around the baby and analyzing the chromosomes in the fetal cells obtained.
  • Both of these procedures involve some risk for pregnancy loss as a procedure related complication, although these risks are quite low.

Down syndrome screening in multiple pregnancies using first- or second-trimester maternal blood markers is less accurate than in single pregnancies.

First-trimester nuchal translucency ultrasound screening for Down syndrome can be done in twin or triplet pregnancies but has some limitations.


Sources:

  • D.E. Battaglia, et al: Influence of maternal age on meiotic spindle assembly in oocytes from naturally cycling women. Human Reproduction October, 1996; (Vol. 11): Pages 2217-2222.

  • S. Lelanda, et al: Heterozygosity for a Bub1 mutation causes female-specific germ cell aneuploidy in mice. PNAS August, 2009; Pages 12776-12781.

  • The American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin #77, "Screening for Fetal Chromosomal Abnormalities.

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