Physician-To-Physician Consult

Dear Colleague

A 33 yo G3 P0 SAB3 with 4 years infertility.
Three very early pregnancy losses at age 30 (all before 6 weeks, no D+C needed, at least 2 were chemical pregnancies).

Karyotypes on both partners were normal
Female partner has two sisters who are both pregnant or have children.
Male partner has two brothers but they have not tried to conceive yet.

Two monitored letrozole cycles with timed intercourse. No pregnancy.

In June 2012 had first IVF cycle with 18 oocytes retrieved, 8 normally fertilized, and 6 blastocysts (mostly 3AA).
PGS done using SNP microarray and 3 euploid, 1 abnormal (Del/Dup 14) and 2 no signal
Three frozen embryo transfers done (one eSET, one DET with tested euploid embryos, and one DET with blastocysts with no signal) under ultrasound guidance with no difficulty. No pregnancy.

Repeat ICSI cycle in April 2014 with 30 oocytes retrieved and 18 good quality blastocysts on day 5. Ten blastocysts biopsied for PGS and 8 unbiopsied all vitrified.
PGS by qPCR showed 9 of 10 blasts were euploid and one was trisomy 18.
FET of one tested normal blastocyst after endometrial biopsy that showed in phase endometrial dating and intralipid infusion on cycle day 8. No pregnancy

Couple decided to use gestational carrier.
One biopsied normal 4AA blastocyst transferred to a 33 yo GC with three healthy children.
Pregnancy confirmed but obstetrical ultrasound at 7 weeks GA showed CRL one week behind dates (6 weeks GA), a yolk sac that was enlarged (6.3 mm) and FHR of 109 BPM.
Repeat ultrasound at 9 weeks showed no fetal growth (CRL consistent with 6 weeks, no fetal heart beat and no yolk sac visualized.

Robert F Casper

View Answers

Answered by Gab Kovacs

"If at first you don't succeed, try, try again."

With several euploid blastocyst vitrified, I would transfer one at a time. I would recommend natural cycles if use has 26-32 day cycles, or HRT ( oestradiol vale rate and progesterone pessaries) if use has irregular cycles.
I would use the KISS principle (Keep It Sort and Simple), and would not spend money on unproven "add ons". My experience is that if you keep throwing embryos at the wall of they uterus, eventually one will stick. I would definitely transfer thenm as eSET, as this gives the best chance for a take home baby.
I see no rationale for a surrogate.

Answered by Norbert Gleicher

Impossible to say for sure what is going on. My gut feeling tells me that it is an embryos problem, even though her embryos are euploid. Just because an embryo is chromosomally normal does not mean it is biologically normal. I think it is more likely egg-related. And here is why:
This patient, considering her egg numbers in IVF, is a PCOS phenotype. My wild guess is that she is a "skinny" PCOS. I further guess that when you run her AMH, testosterone levels and SHBG, you will find that her AMH is high, her testosterone is, however, quite low (her DHEAS may be especially low) and her SHBG will be high.
If my predictions turn out to be correct, then you have on hand a new patient group we recently identified (a manuscript was just submitted) who we, here at CHR, have come to call "burning out" PCOS patients. They present with above described lab picture, which means that, considering that PCOS patients usually have high androgens, their androgens are particularly low. They, therefore, need androgen supplementation (DHEA) because their ovaries are "used" to higher androgen levels from younger years! With androgen supplementation they not only raise their testosterone and DHEA-S but also decrease their SHBG, which will tell you when their testosterone is high enough.
If you start IVF cycles at that point, they will give you 'better" eggs and embryos,
These patients are statistically also very frequently showing immune/inflammatory abnormalities, and, therefore, may require immunosuppression with prednisone and, sometimes, in the most severe cases, IV-Ig to prevent pregnancy losses (we are not big fans of intralipid, and use it only as a 2nd choice if patients can't afford IV-Ig).
These patients often also have low FMR1 alleles (<26 CGG repeats), which, if present, reduce their expected IVF pregnancy chances by ca. 40%. Finally, if we are correct, this patient in relatively short time will be dropping her AMH levels significantly and, soon, may be a patient with relatively low ovarian reserve, suggesting premature ovarian aging (POA).
Let me know whether my lab predictions are correct.

Answered by Sherman Silber

1) transfer all embryos she has so far.

2) if all miscarry or do not result in pregnancy or viable pregnancy,

3) patient will then be emotionally ready for what i am sure will be the eventual solution, donor eggs.

Answered by Robert Fischer

I will suggest to check the male for DNA- fragmentation. He might have a high fragmentation rate which might cause bad quality embryos even if they are euploid and that might affect pregnancy rate and increase miscarriage rate. If DNA fragmentation is high one should try by changing life-style, Vit D, exclude Insulin resistance and so on... to reduce the fragmentation index and also using hyaluronic acid(PICSI) or MAC or IMSI to try to select unaffected sperm for the ICSI.
I hope it might be useful-we had a few cases like that as well and we solved it this way

Answer by Ariel Weissman

Difficult case indeed. Since both the patient and the gestational carrier miscarried, more attention should be given to the sperm. It is hard to believe that there is a big problem with the sperm since it fertilized without ICSI in the first cycle, and good quality blastocysts formed in both cycles. Nevertheless, as Robert Fischer suggested, check the sperm DNA frag index and if the DFI is high, treat with vitamin E for 3 month and repeat the testing. If DFI is still high, use testicular sperm obtained by TESA for ICSI.
After excluding immunological and autoimmune disturbances, thrombophilia (I assume hysteroscopy was normal), go on replacing single frozen-thawed embryos in natural cycles. Consider empiric treatment with LMW heparin after ET. I doubt the need of a gestational carrier, but of course it would not be a mistake to try again with her.
Good luck, please let us know how this story ends...

Answer from PC Wong

Difficult situation.
I assume hysteroscopy is normal. I will continue with repeated thaw DET and hope for the best.

Answered by John Yovich

I have data, yet to be published, supporting:
Hysteroscopy with correction of subtle uterine anomaly such as:

T-model: ie T-configuration cavity with prominent isthmus shoulders

Mercedes Benz: ie sub-arcuate or sub-septate cavity.

Mazda model: Prominent isthmic shoulders plus sub-arcuate fundus

I have ultrasound pictures available for these 3 uterine cavities resembling automobile logos.

I can send them in if Zeev wishes to publish more widely (without RCT).

Implantation rates are higher after correction. I believe results are better than simple "Swizzle Stick" i.e. endometrial Bx.

All corrections easy and safe; no harm in trying!

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