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Embryo Selection after IVF

Embryo Selection after IVF

Embryo Selection after IVF

Many of human embryos produced after in vitro fertilization carry abnormal chromosomes. Placing a chromosomally normal embryo (s) into a normal uterus has a very high chance of achieving a pregnancy. Your eggs have been retrieved and the mature eggs were fertilized. Now You and your reproductive endocrinologist are faced with the critical task of how many and which embryo to transfer to the uterus or which ones to freeze.

Why do we Need Embryo Selection?

Selection of the most appropriate embryo(s) for transfer aim at i. Maximizing the chance for pregnancy and ii. Minimizing the risk of twins and other multiple pregnancies. Casual inspection of the embryo does not yield accurate information about its chromosome makeup. One can follow an indiscriminate approach where all embryos are transferred. The problem is this approach yields high unacceptable multiple pregnancy rates. On the other hand one can transfer one embryo at a time. This is a much safer approach in terms of markedly minimizing twin rates but may lower the chance for getting pregnant. In addition it also require a robust freezing program so that frozen embryos can survive thawing. Right now in The US the survival of frozen embryos exceed 95% and the chance for pregnancy with a thawed embryo is approximately equal to a fresh embryo.

Measure of Success: time to conceive or cumulative chance for pregnancy?

One major issue related to fertility treatment especially IVF is how to measure success? specifically consider this question: if you have three embryos and decided to transfer them one at a time and got pregnant after the third transfer with a singleton, how does that compare to transferring all embryos in the fresh cycle and getting pregnant in twins? before answering it is important to know that twin gestation is associated with higher risk for pre-term delivery, ICU admissions and long term consequences for the babies.

In other words should you consider success as pregnancy taking place after one retrieval (cumulative chance from fresh and frozen embryos) or pregnancy taking place in the fresh cycle only (fresh embryos)? In other words would you like to shorten the time to conceive at the expense of higher risk for multiple pregnancy? Within reason, this is a question for you and your reproductive endocrinologist to answer based on your preferences and his practice

You have a Voice: How should you use your embryos after IVF?

You need to have a voice in the number of embryos transferred to your uterus. Although your fertility specialist can discuss numbers and chances and other technical details as well as long term risks for multiple pregnancy, there are questions that cannot be answered by anyone but you.

  • How do you feel about twins? triplets and quads?
  • Would you accept fetal reduction (removal of one or more sacs from the uterus and leaving only one or two)?
  • Do you have the social support system to take care of twins?

For these and many other reasons your input in the number of embryos to transfer is paramount.

Methods of Embryo Selection after IVF

Embryo Morphology and Female Age

Age is, by far, the strongest predictor of the health of the embryos. Younger women produce more chromosomally normal embryos than older women. An embryo from a woman at age 30 commonly implants 40% of the time as opposed to 5% or less in a woman age 40. For any given cohort, embryos are graded based on specific morphological criteria from the best looking to the worst. These criteria are technical and followed by all embryologists. Embryos are prioritized for transfer based on their shape. Morphology, however is may be 50 to 60% predictive of pregnancy, far from ideal. The combined use of morphology of embryos, stage of development (day 3 or blastocyst) and age is the standard selection method for which embryo is transferred first and how many. This method has the advantage of being sheep, quick and non-invasive. All other methods must prove superior to morphology + age before adoption.

Extended Culture to Blastocyst Stage (Day 5 Embryo)

Keeping day 3 embryos in culture may give these embryos may time to develop to blastocysts. Presumably, the better embryos progress to blastocysts or do so faster than less healthy embryos, thus they are preferentially selected for transfer.

Time Lapse Imaging of Embryos

time lapse embryo imaging-normal embryo division

time lapse embryo imaging-normal embryo division

Embryos are placed in a specific incubator in a specific plate and is observed at predetermined time

time lapse embryo imaging-abnormal embryo division

time lapse embryo imaging-abnormal embryo division

points using time lapse microscopy / photography. Photos are analyzed manually or through a computer and embryos are graded based on timely division of blastmeres (component cells). There is no evidence so far that pregnancy rate is improved above using morphology. There is extra cost associated with the use of the special plate and is also limited by the number of special incubators available.

PGS (Embryo Chromosome testing)

New forms of PGS (performing biopsy at the blastocyst stage) and more accurate platforms for analyzing the biopsied cells are available. However, the concept that better selection will lead to improved IVF results is far from certain.

It success of an IVF cycle is measured after transfer of fresh then frozen embryos till pregnancy ensues (cumulative success) ad patients are will to be patient for 1-2 more months, then any form of embryo selection, PGS or otherwise, will not improve the live birth rates. Moreover, PGS can be harmeful as it may misdiagnose the health of the embryos (see this article on PGS for details). PGS increases the expense of treatment $4000 to 6000

Embryo selection is maybe be able to improve the time to pregnancy, if embryos with the highest implantation potential are transferred first.

Based on the available evidence, judicious selection of embryos based on patient age, morphology and the use of extended culture to blastocysts are the standard of care in embryo selection after IVF. Two additional factors to consider is how robust is the freezing program of that specific lab (generally excellent all over the US) and the acceptability of fetal reduction by the couple. Liberal use of single embryo transfer when appropriate should be strongly considered. ‘New’ ideas should be subjected to rigorous scientific evaluations ‘fertility clinical trials’ before they are ready for routine use. Thus far, based on published evidence, embryo time lapse imaging and PGS should remain investigational.

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Should you Test Embryos created after IVF if You had Recurrent Miscarriage?

Should you Test Embryos created after IVF if You had Recurrent Miscarriage?

PGD Recurrent Miscarriage

1. Early pregnancy loss approximately < 10 weeks, mainly due to chromosomal abnormalities of the embryo and

2. Late pregnancy loss ≥ 10 weeks due to structural uterine abnormalities, hormonal factors, blood clotting abnormalities, immunological factors and chromosomal abnormalities of the embryos (less likely than early loss).

Women with history of recurrent miscarriages should be tested for all these factors before a fertility treatment plan is finalized.

Factors that point to chromosomal abnormalities as a cause for recurrent miscarriage

  1. Advanced maternal age,
  2. Diminished ovarian reserve (e.g high FSH, low AMH),
  3. Early pregnancy loss before a fetal heart activity is detected (chemical pregnancy, blighted ovum),
  4. Abnormal chromosomes of the products of conception and
  5. Abnormal chromosome configuration of male or female partner e.g chromosome translocation. Less than 5% of couples miscarry due to a translocation in the male or female partner.

Structural abnormalities of the uterus are detected using saline sonography, hysteroscopy or MRI scan. Blood tests can detect hormonal abnormalities, clotting abnormalities and immunological factors.

Should you Test Embryos created after IVF if You had Recurrent Miscarriage? (if chromosomal abnormalities of the embryos are suspected)

Factors to consider before deciding to test embryos:

  1. Embryos should probably be tested in women or men that carry abnormal chromosome configuration e.g. translocation as they produce higher proportion of abnormal embryos than parents of the same age
  2. Embryos should be tested if avoiding another miscarriage  is a priority, especially if prior miscarriages took place later in the first trimester and required surgery. Repeated scrapping of the uterus can damage the lining that may be difficult to treat (Asherman syndrome).
  3. There is no prove that PGD for chromosomes will improve the chance for conceiving a normal child. PGD will only detect what you have and is not a therapeutic procedure. The decision for embryo testing using PGD should be individualized for all other parents. Older women may not have any normal embryos to transfer after testing. Although testing may avoid a pregnancy with an abnormal embryo that implant and survive >10 weeks, the majority of abnormal embryos do not implant or are miscarried extremely early.

Just because it is available, sounds plausible and you have the means to do it, does not mean you should test your embryos prior to IVF.

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Sex Selection

Sex Selection

Sex selection is considered for one of three reasons:

1. Avoiding sex related genetic disorders. These are genes mostly carried on the X chromosomes and affect boys more than girls since they have one X chromosome e.g hemophilia

2. Family balancing: couples that have children of one sex and desire a child of the opposite sex

1941-2011 Trend: Suppose you could only have one child. Would you prefer that it be a boy or a girl?

Gender Selection, Boy or a Girl

3. Preference: some prefer a child of certain sex due to social factors. Recent poll in The UK  indicates that when 2,129 recently married couples were surveyed, found that 47% admitted that they would prefer to have a son first, with the majority citing practical reasons like boys being “less hard work”. Only 21% of respondents said they would like to have a daughter as their firstborn, and 32% reported having no preference either way. Couples who wanted to have a daughter first see older girls as ‘better role models’ to their younger siblings. In the US a Gallup poll yielded similar answers by American parents, especially men, since 1940s. American women do not have a proportionate preference for girls. American women show essentially no preference either way: 31% say they would prefer a boy and 33% would prefer a girl. More recent trends indicates that American couples prefer girls.

In contrast couples on a waiting list for adoption prefer girls both in the US and India. There is also some evidence that sexual orientation may influence that preference. Gay men are more likely to have a gender preference for their adopted child whereas heterosexual men are the least likely. Couples in heterosexual relationships are more likely to prefer girls than people in same-gender relationships.

The preference is also influenced by geography and politics. The official family planning policy in China, applied to large portions of Chinese, allow only for one child and does not allow sex selection. In the US many couples desire to limit the number of children to 2. If the first child is of one sex they desire the second child to be of the opposite sex

 

How is the sex of the embryo determined?

Older methods of selecting sex through change in the position or timing of intercourse or sperm sorting are not accurate and are not suitable for sex selection in modern couples seeking a specific sex (the other sex maybe conceived in 30% or more of couples). Modern sex selection depends on genetics. After stimulation of the ovaries, egg retrieval and fertilization, one or few cells from the embryo is obtained. The cells are analysed for each embryo for the X and Y chromosome. Results are obtained and are accurate >99% of the time.

After identification of the X and Y chromosomes, the desired embryo is transferred into the uterus. The embryo that carries the correct chromosome, should survive and be of good quality. Sex selection is more likely to succeed in women with good ovarian reserve, producing a good number of eggs. The larger the number of embryos available for testing, the more likely a healthy embryo of the desired sex is available for transfer.

Learn more about gender selection.

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Should You Test Embryos Created after IVF for Chromosomal Abnormalities?

Should You Test Embryos Created after IVF for Chromosomal Abnormalities?

Many of the embryos created after IVF carry abnormal chromosomes. Normal embryo cells carry 46 chromosomes. The most common abnormalities are extra chromosome e. +21 (47 chromosomes) or missing a chromosome e.g -X (45 chromosomes). By far, abnormalities in the egg is the source of abnormal chromosome number.

Preimplantation genetic screening (PGS)

PGD: Testing of embryo chromosomes

Finding a ‘normal’ embryo is clearly advantages as it will theoretically lead to 1. The transfer of a single embryo instead of many  embryos and  2. can produce higher pregnancy rate than an embryo selected based on morphology (looks) alone. The process of embryo testing for the purpose of improving pregnancy rate is, however, not simple in relation to the accuracy of testing and many other issues

Preimplantation genetic screening for chromosomal abnormalites (PGS)

PGS require two steps: 1. Biopsy: obtaining a cell or a group of cells from the embryo and 2. genetic testing of the cells for chromosomes ideally in 1-2 days to obtain results and allow fresh transfer

Biopsy

Day 5 embryo biopsy

Biopsy of trohoectoderm cells of blastocyst

Obtained by removing a. a single cell of a day 3 embryo or  b. group of cells from the trophoectoderm (the outer part of the embryo that makes the placenta) of a day 5 embryo (blastocyst). Removal of cells nowadays uses a laser beam. Cells are fixed on a glass slide and sent for analysis.

Genetic Analysis of Embryos

In the past old technologies (FISH) was limited in its ability to test all chromosomes. Multiple studies in the past few years proved that PGD using FISH actually reduce the chance for pregnancy in many IVF populations and should not be used. Two newer technologies can test all the chromosomes in an embryo: cGH (comparative genomic hybridization) array and SNP (single nucleotide polymorphism) array. Some of these methods can report the results in 3 days allowing for delayed fresh transfer (day 6) and others require about a month for accurate testing, necessitating embryo freezing and transfer in frozen-thaw cycle. Labs offering these methods claim accuracy of 95 to 97%. There are more advanced methods e.g genome screening, that can test embryo chromosomes in as short as 6 hours. The ultimate method for testing is still evolving.

Should women test their embryos before transfer to the uterus?

My short answer is no, not routinely. The pros of testing embryos could be transferring less embryos , improving IVF outcomes (pregnancy rates) and avoiding pregnancy with a baby carrying chromosomal abnormalities. The cons are these aims are still not proven facts due to

1. The biopsy may hurt the embryo, reducing its ability to implant

2. The assumption that one cell represent the whole embryo may not be true (mosiacism); the cell may be abnormal while the rest of embryo is normal or vice versa

3. The methods of testing was not validated by independent large studies from multiple centers and maybe less accurate than claimed

4. Delay in transferring the embryo in the fresh cycle may reduce its implantation potential

5. Cost associated with biopsy and testing the embryo is approximately $5500 to $8000

6. Testing of an embryo will not improve the ‘pregnancy’ potential of that embryo. It will just tell you if the embryo is ‘normal’ or not. The potential from all the embryos obtained from IVF after an egg retrieval is not changed by testing. Assuming a very accurate test and an excellent freezing program,  tested embryo transfer should yield similar outcome as transferring untested embryo(s) in multiple cycles. That is the most important point to consider. If you are willing to be patient and transfer one or few embryos resulting from one ovarian stimulation successively in the fresh cycle then frozen cycles, the cumulative pregnancy and delivery rate should be the same at the end. For example in young women transferring one embryo, approximately 30- 40% of them will just achieve pregnancy in the fresh cycle. In the first frozen-thaw transfer another 30% or so will get pregnant. Frozen cycles are not as demanding as fresh IVF. Many women can have the embryo transferred in a natural cycle with no medications and minimal monitoring.

Embryo testing may help younger women, producing a large number of embryos and want to transfer only one. An alternative approach is to transfer one embryo at a time as their pregnancy rate is high even with a single untested embryo.

Testing of embryos from older women (40 or older) producing few embryos  (<6) is of little value as the alternative is to transfer 5 or so untested embryos in that age group because of the very high rate of chromosomal abnormalities in the embryos.

Testing may be helpful for older women (40 or older) producing a very large number of embryos (e.g >10 embryos) to eliminate the need for multiple transfers to get to the healthy embryo. This category (older women and very large number of eggs / embryos) is rare in IVF population.

Women contemplating testing of their embryos after IVF should consider many issues including age, number of embryos, history of unsuccessful fertility treatment if any, cost and sometimes tolerance for multiple pregnancy and fetal reduction. Moreover women should consider all these factors and be ready to modify their decision during the cycle depending on the number of available embryos.

All this does not apply to women testing the embryos for chromosome translocation, a specific genetic disease or sex.

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