December 12, 2017

Were the octuplets a result of IVF?

When I first heard about the octuplets who were born earlier this week, my first theory of how this came about was that somebody went to Tijuana, bought fertility drugs, injected herself indiscriminately without medical supervision and then went on to have sex. According to the latest updates, this may have been a result of IVF. This news comes as a huge shock for several reasons.

In the first scenario I described, it is feasible to think that somebody injected herself with medication, unmonitored and unaware of exactly how many follicles she was developing. Therefore it would be more understandable that she subjected herself to the risk of octuplets when in fact, she thought she had much fewer eggs. However, if it is true that these babies are a result of IVF, that brings up many questions.

It’s one thing to post flyers announcing a party at your house and then being surprised when 100 people show up. It’s entirely another thing to send out 200 personalized invitations and then being surprised when 100 people show up. In other words, when you take fertility drugs and have an insemination or just have sex, you might not know how many eggs are actually growing. You would need to monitor using ultrasound to get an idea of how many eggs there could be. Even if you did monitor and count the follicles, it’s still uncertain how many eggs will physically wind up in the right place. With IVF, it’s an entirely different matter. In this case, an exact number of embryos are transferred right into the uterus. Therefore, in order to have eight, someone would have to deliberately and knowingly put eight or more embryos into uterus. Why? That’s the big question.

One of the most important decisions in IVF is how many embryos to transfer. In general, the more embryos you transfer, the higher the chance of success, but also the higher the chance of multiple gestation. The goal is to maximize the chance of having one or two babies. Zero is not good. Three or more is certainly not preferred either.
In order to understand the thought process that goes into deciding how many embryos to transfer, let’s use a deck of cards as an example. Pretend that you have a well-shuffled stack of 1000 cards and you were told that in each deck, some cards are green and some cards are red. You are then given a very specific deck of which exactly 50% were green cards and 50% were red cards. And then you are told that for every green card you draw, you get one baby. For every red card you draw, you get nothing. Now you are asked. “How many cards would you like to draw?” If you decide to draw just one card (ie put in one embryo) then you have a 50% chance of coming away with nothing and a 50% chance of coming away with a single baby. The math is simple on that one.

Let’s say however, instead of drawing one card, you decide to draw two. Now, you will wind up with a 25% chance of no babies, 50% chance of one baby and 25% of twins. This is a very popular choice for many couples. The exception would be couples who are very much against having twins. Then they would be more conservative and prefer only transferring one. On the other extreme, couples who are very aggressive may prefer to put in three rather than two. What happens in this case if we put in three?
Chance of zero babies: 12.5%
Chance of one baby: 37.5%
Chance of twins: 37.5%
Chance of triplets: 12.5%
By putting in that third embryo, you have reduced the chance of a completely failed cycle from 25% down to 12.5%. You have lowered the chance of a single baby from 50% down to 37.5%, and you have raised the odds of twins from 25% to 37.5%. You have also increased your risk of triplets from zero to 12.5%.

When people ask me “How many embryos should I transfer?”, my answer would be “It depends.” It depends on how aggressive you want to be. What do you fear more? A completely failed cycle? Or a cycle where you end up with more than twins. It also depends on what is the estimated % of success for each embryos, ie what % of cards are green? The final variable is “What actions are you prepared to take in the event of getting quadruplets or more?”

So let’s take what the news has reported regarding these octuplets. This is a woman, supposedly in her early 30’s with a history of having six children on her own. Those are fairly favorable condition. Let’s say that the embryos in question were blastocyst embryos and that we estimate (generously) that each embryo has a 60% chance of becoming a baby. If you were to transfer eight embryos that each had a 60% chance of becoming a baby, then what are your possibilities?
Chance of zero babies: 0.07%
Chance of one baby: 0.79%
Chance of twins: 4.13%
Chance of triplets: 12.39%
Chance of quadruplets: 23.22%
Chance of quintuplets: 27.87%
Chance of sextuplets (6): 20.90%
Chance of septuplets (7): 8.96%
Chance of octuplets (8): 1.68%

Just to clarify, what I have just listed are the predicted outcomes if you put in eight embryos, each with a 60% chance of “taking”. As you can see, there are a few odd things. When you put in eight, the odds of all eight taking are actually quite low at 1.68%. So when the patient’s family member said they were surprised that all eight took, that has a teeny bit of validity. However, that validity flies out the window when you realize that even though the chance of all eight taking is small, the chance of four, five, six, or seven taking is cumulatively 80.95%. So how can anyone justify putting in eight embryos when the odds of quadruplets or more is so overwhelmingly high.

We also can infer from these calculations that if this truly was IVF, then it’s quite possible that even MORE embryos than eight were transferred so that eight actually took.

OK, for the sake of argument, let’s say that whoever made the decision on transferring so many embryos felt in his heart that each embryo only had a 25% chance of implanting. Would that justify putting in so many embryos? Let’s do the calculations…
Chance of zero babies: 10.01%
Chance of one baby: 26.70%
Chance of twins: 31.15%
Chance of triplets: 20.76%
Chance of quadruplets: 8.65%
Chance of quintuplets: 2.31%
Chance of sextuplets (6): 0.38%
Chance of septuplets (7): 0.04%
Chance of octuplets (8): 1 out of 65,536!

In this case, it’s a bit more reasonable, but still very very risky given that the chance of quads is 9% and the chance of triplets 20.76%. But if this were the case, then this octuplet birth would really be a miracle in mathematical terms because it would have really defied the odds.

We don’t have all the facts and it’s well possible that the family members providing the new information were mistaken or just not telling the truth. In any case, we in the RE community are waiting a little nervously to see how this all plays out. Our fear is that the powers that be will seize this extreme case use it as an opportunity to put draconian restrictions on physicians in this field, despite the fact that the majority of us have not been careless.

  • http://unyielding.blogspot.com/ Syn

    Is it possible that four were placed and all four split?

  • IVF-MD

    Yes, possible, but by rough estimate less than 1 in a billion chance.

  • Jayne

    Just watched your clip on KCAL 9. Thanks for sharing!

  • http://www.mloknitting.com/ MLO

    This story is getting more and more bizarre:

    http://news.yahoo.com/s/ap/20090131/ap_on_re_us/octuplets

    Now, I know, and participated in a study where participated in a study where drug costs were defrayed. I have never heard of someone in the USA getting paid to have their own IVF cycle.

    Also, traditionally, aren’t embryos frozen in “packs of two”? If this really was an FET, why on earth would they thaw eight? I don’t think there is any clinic that has an unreasonable storage fee considering the actual technology and energy costs involved.

    I am also not convinced that this was done in an American clinic. Though, the bizarreness of this story is making me wonder if it was a less than legitimate clinic that was involved (not a SART member or close to being fined or even closed by the CDC.)

  • IVF-MD

    You are so right.

    Here are some additional thoughts. If she were an egg donor, she could have done a shared-cycle arrangement where she was paid to donate AND was given control over some of the embryos for her own use. This is unlikely, because it’s usually one or the other. We can’t really rule out the fact that some of the statements from the mother or from her family are inaccurate.

    Embryos are frozen as singles or pairs. If for some crazy reason, hers were frozen all together as eight, there is still the option of thawing them, transferring two or three and then refreezing the rest. Not optimal, but possible.

    It’s really a mystery how this came about, but I am not so sure that this was a foreign IVF program. As we find out more, we can comment further on what sanctions might be taken.

  • fujinkai

    Dr. Lee,

    I really liked your clear explanation of the chance of singleton or multiple pregnancy. I also liked how statistically it looked like it was being modeled after a Fibnocci sequence. Is there anything published on using this as a counseling method on chance of a multiple pregnancy?

  • IVF-MD

    Thank you for the kind words. The math is a simple binomial distribution. The model is a simplified representation of the reality, for several reasons. I have a blog post that I’ll finish some day on this. One of the most obvious reasons that this model is less than perfect is that when you transfer 3 embryos, not all three have the exact same odds of implanting. You might have an 8-cell embryo with no fragmentation and then two 5-cell embryos with moderate fragmentation. This will mean that each embryo has different odds of success. The main imperfection of this whole model is that we don’t really know the exact % chance of success per embryo. We can only estimate it based on patient’s age, patient’s past history, stage of embryo, degree of fragmentation and cell number. One other flaw in the model is that the chances of each embryo implanting are not truly independent. For example, in the unfortunate event that you have a traumatic transfer, you will end up hurting the chances of ALL the embryos. If you have a perfect “10-point landing” transfer, then you boost the odds of all the embryos, leading to a skew towards the more extreme outcomes of no implantation or all implanting. I use these calculations sometimes when counseling patients, but I have never seen it published. I came up with it myself, based on my love of math and probability theory.