AskNat The column where you ask and I answer like the doctor-friend you wish was in the room with you. Real questions from real women, straight from my inbox. General education, never a substitute for your own doctor.
Your questions this week are great, and some of you were asking very similar things! As always, these are real questions from your submissions, cleaned up so no one is identifiable, and answered the way I would if you were sitting across from me. I will tell you what I tell my own patients—explaining what we know and what we don’t. This is not personal medical advice, and I am not your doctor. But you deserve to understand your body, and that is what we are here to do.
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Questions answered this week:
“Can you discuss mosaic embryos and their success rate? Which mosaic embryos would you prioritize first?”
“My luteal phase is 9 days. Is this normal?”
“I just had a chemical pregnancy and I’m so scared to try again, but I feel like I should because I read on your Substack that chances are higher after. Can you tell us more?”I just had a chemical pregnancy and I’m scared to try again (and is it true chances go up after?)
“What’s a safe dose of inositol in pregnancy and breastfeeding? I have PMOS and a history of gestational diabetes, and took 1 g/day (myo-inositol) last pregnancy with no side effects.”
A mosaic embryo is an embryo that had genetic testing and came back essentially with a mixed result—some normal cells and some cells that are abnormal. There are different types of mosaic embryos, so this is a really good question.
When we do preimplantation genetic testing for aneuploid (PGT-A), we take a biopsy of around 5-8 cells from the trophectoderm (the cells that become the placenta). Each cell is then evaluated to see if it is genetically normal or not. Note, unless we are looking at PGT-M, which is an extra layer of screening, then we are not looking at single gene disorders (like the gene that carries cystic fibrosis or the gene that carries the BRCA mutation). For PGT-A we are simply evaluating if the cells have the normal number of chromosomes, or is part of a chromosome is missing or duplicated.
The two main type of mosaic embryos include low level mosaic embryos and high level mosaic embryos. The easiest way to think about this is that low level mosaic (LLM) embryos have most the cells normal and a high level mosaic has most the cells abnormal (HLM). Now, in the early days of PGT-A, the labs didn’t report out LLM vs HLM instead everything was grouped as either ‘normal” or “abnormal” and in this time LLM embryos were put into the “normal” group and HLM were put in the “abnormal” group. Since we now detect and report mosaicism, we see the highest birth rates with embryos that are genetic euploid (normal) or about 65% per transfer.
LLM embryos should be considered for transfer but as a second line, with a cumulative live birth rate of around 30%—which is still a good number, but lower than euploid embryos. HLM embryos have a much lower love birth rate (usually around 5% or less) and many clinics will not transfer these embryos. We prioritize small chromosome defects (segmental breaks) over whole chromosome abnormalities, and there are some chromosome defects that may not be worth the risk.
We have patients see a genetic counselor who specializes in embryo testing and a high risk MFM prior to transferring a mosaic embryo. Sometimes patients decide to proceed with fetal testing (like an amniocentesis) if they get pregnant to get a confirmatory karyotype of the baby if the PGT-A was a mosaic embryo. Note, a CVS sampling also tests the placenta so that would not be appropriate in this case because the same tissue line is being testing for both.
All that said, it does depend which chromosome the defect is on and what type of abnormality it is. We now know that embryos which come back as segmentally aneuploid still have a live birth rate of over 20%! So even not all “abnormal” embryos are created equally and we have to think about where the chromosome issue it.
Remember that when we take a biopsy of an embryo we are taking 5-8 cells out of hundreds. It is a blind snapshot and may not reflect the actually fetal cells (since we are taking the biopsy from the cells that become the placenta). Also complicating the picture is the fact that the embryo is still growing and developing and can self correct itself—sometimes pushing out abnormal cells so the embryo inside is healthier. This is the problem with a mosaic embryo, when we have 2 cell lines we don’t really know which one reflects the status of the baby.
The good news is that many perfectly normal children have been born from mosaic embryos, and probably from well before we even knew we were transferring them! If you do PGT-A, I would prioritize transferring 1) euploid embryos first, 2) LLM with partial chromosome abnormalities 3) LLM with whole chromosome abnormalities, 4) segmental aneuploid, 5) HLM. Of course, anytime the PGT-A comes back as anything except euploid, you should ask to talk to genetics, even if not required by your clinic. This will set you up to be in the best position to get the data you need to have to make an informed decision.
A 9 day luteal phase is not normal. A short luteal phase is defined as a luteal phase of less than 11 days. If we think back to the menstrual cycle, the lute, phase is a sign of normal ovulation. A follicle grows as the egg matures, the follicle ruptures and the egg ovulates, then the follicle reforms and becomes the corpus luteum making progesterone. This entire process is under direct control of the brain, which is highly sensitive to the world around you.
A short luteal phase is the first stage of ovulatory dysfunction. Meaning this: if you don’t grow the best follicle (which becomes the foundation for the corpus luteum), you won’t have a great corpus luteum. Said another way: if the brain can’t stimulate the follicular and ovulatory phase, I’ve lost confidence we can send out enough LH to support progesterone.
There are some medical reasons for a shorty luteal phase: thyroid disease, elevated prolactin, hypothalamic dysfunction (which encompasses energy deficit, chronic stress, chronic inflammation and even insulin resistance). Sometimes a short luteal phase is a sign of low ovarian reserve (although classically we see a shorter follicular phase in this as the first cycle change).
Tests I recommend to start with include: thyroid panel (including antibodies), prolactin, fasting insulin, and AMH. Sometimes the treatment is straightforward, sometimes luteal progesterone treatment (starting 2-3 days after ovulation) or ovulation induction can be helpful.
A chemical pregnancy is one where you get a positive pregnancy test but the pregnancy miscarries prior to seeing it on ultrasound. In the past, some doctors didn’t “count” a chemical pregnancy loss as a “real” pregnancy loss. I call this a lot of BS, and as someone who has had a lot of losses, I never believed this. I am happy to report that guidelines have changed on this one and now all losses count.
In fact, in a study looking at women after a pregnancy loss, women who started trying again at 0-3 months after their loss (as compared to >3 months after their loss) had higher odds of conceiving and conceived faster. There was no higher chance of a second chemical pregnancy after one loss.
After one pregnancy loss, your loss of having another pregnancy loss are not higher. This does change after multiple pregnancy losses, so please consider getting an evaluation if you have had 2 or more losses.
From someone who had 4 losses herself, sending you huge hugs. It sucks, it makes you question everything—your future, your body. But more than anything know that pregnancy loss occurs on average in 1 out of 4 pregnancies, you are not alone.
.PMOS (previously PCOS) is characterized by abnormal insulin metabolism, and inositol is a first-line treatment approach that can be very helpful. Inositol, specifically myoinositol works as an insulin sensitizer and a mainstay in PMOS treatment because better insulin signaling results in improves ovulation and symptoms.
For general PMOS management, the doses studied are usually around 2-4g of myo-inositol per day.
In pregnancy trials, myoinositol at roughly 2g twice daily (about 4 g/day) was used, appeared safe, and was associated with a lower rate of developing gestational diabetes in high-risk groups. So the dose you took last time, 1 g/day, is on the lower end of what’s been studied, and the trial-level dose is higher which should make us feel confident that you haven’t done any harm, and I let my patients continue myoinositol in pregnancy for this reason (to lower the GDM risk).
For breastfeeding, we just don’t have the same data. On the pro side, it is a natural substance and normally present in breastmilk, so generally considered low risk. In fact, early data looks like it may even help improve fetal brain development (win!). That said, we always want to think about the full picture and you should discuss with your doctor.
Overall, inositol is one of the safer options we have for PMOS and it is ok to continue in fertility treatments, pregnancy, and breastfeeding—BUT you should absolutely discuss with your OB-GYN in case there is something about your history or medications that modifies your personal risk.
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Before you go
None of us should have to fail before we understand our own bodies, and none of us should have to figure it out alone at midnight with a search bar. Paid subscribers can submit questions below to have them answered in AskNat.
XO, Nat
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